NM_003227.4:c.2069A>C

Variant names:

• chr7-100626830-T-G
• rs80338889
• NM_003227.4:c.2069A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_003227.4(TFR2):​c.2069A>C​(p.Gln690Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000429 in 1,397,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.79
• Publications: 13 publications found

Genes affected

TFR2 (HGNC:11762): (transferrin receptor 2) This gene encodes a single-pass type II membrane protein, which is a member of the transferrin receptor-like family. This protein mediates cellular uptake of transferrin-bound iron, and may be involved in iron metabolism, hepatocyte function and erythrocyte differentiation. Mutations in this gene have been associated with hereditary hemochromatosis type III. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2011]

TFR2 Gene-Disease associations (from GenCC):

• hemochromatosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

LOC124901709 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 7-100626830-T-G is Pathogenic according to our data. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-100626830-T-G is described in CliVar as Pathogenic. Clinvar id is 5384.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4	c.2069A>C	p.Gln690Pro	missense_variant	Exon 17 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3	c.1556A>C	p.Gln519Pro	missense_variant	Exon 14 of 15		NP_001193784.1
LOC124901709	XR_007060454.1	n.433+4276T>G		intron_variant	Intron 1 of 2
LOC124901710	XR_007060455.1	n.-80A>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.2069A>C	p.Gln690Pro	missense_variant	Exon 17 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000429 AC: 6 AN: 1397372 Hom.: 0 Cov.: 36 AF XY: 0.00000580 AC XY: 4 AN XY: 689376

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5548

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078966

Other (OTH) AF: 0.0000345 AC: 2 AN: 57970

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hemochromatosis type 3 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.68	T;.
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.90	L;L
PhyloP100		2.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.21
Sift	Benign	0.17	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.21	B;B
Vest4		0.74
MutPred		0.81		Loss of MoRF binding (P = 0.0777);Loss of MoRF binding (P = 0.0777);
MVP		0.68
MPC		0.52
ClinPred		0.61	D
GERP RS		5.3
Varity_R		0.62
gMVP		0.87
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338889; hg19: chr7-100224453;