rs786204108

Variant names:

• chr7-100626866-C-G
• rs786204108
• NM_003227.4:c.2033G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-100626866-C-G
• chr7-100626866-C-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_003227.4(TFR2):​c.2033G>C​(p.Arg678Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000086 in 1,395,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R678R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.63
• Publications: 1 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: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia

LOC124901709 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 7-100626866-C-G is Pathogenic according to our data. Variant chr7-100626866-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 188153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	NM_003227.4	MANE Select	c.2033G>C	p.Arg678Pro	missense	Exon 17 of 18	NP_003218.2
	TFR2	NM_001206855.3		c.1520G>C	p.Arg507Pro	missense	Exon 14 of 15	NP_001193784.1	Q9UP52-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TFR2	ENST00000223051.8	TSL:1 MANE Select	c.2033G>C	p.Arg678Pro	missense	Exon 17 of 18	ENSP00000223051.3	Q9UP52-1
	TFR2	ENST00000855275.1		c.2129G>C	p.Arg710Pro	missense	Exon 19 of 20	ENSP00000525334.1
	TFR2	ENST00000855257.1		c.2033G>C	p.Arg678Pro	missense	Exon 18 of 20	ENSP00000525316.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000860 AC: 12 AN: 1395402 Hom.: 0 Cov.: 36 AF XY: 0.00000581 AC XY: 4 AN XY: 688520

African (AFR) AF: 0.00 AC: 0 AN: 31588

American (AMR) AF: 0.0000280 AC: 1 AN: 35768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25162

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5408

European-Non Finnish (NFE) AF: 0.0000102 AC: 11 AN: 1079106

Other (OTH) AF: 0.00 AC: 0 AN: 57946

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hemochromatosis type 3 (3)
1	-	-	Hereditary hemochromatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		6.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.75		Loss of MoRF binding (P = 0.0043)
MVP		0.83
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.99
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786204108; hg19: chr7-100224489;