chr7-100626866-C-G

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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 (★★).

• 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

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]

LOC124901709 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 188153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100626866-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4	c.2033G>C	p.Arg678Pro	missense_variant	Exon 17 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3	c.1520G>C	p.Arg507Pro	missense_variant	Exon 14 of 15		NP_001193784.1
LOC124901709	XR_007060454.1	n.434-4290C>G		intron_variant	Intron 1 of 2
LOC124901710	XR_007060455.1	n.-116G>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.2033G>C	p.Arg678Pro	missense_variant	Exon 17 of 18	1	NM_003227.4	ENSP00000223051.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hemochromatosis type 3 Pathogenic:3

Oct 06, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 14, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hemochromatosis Pathogenic:1

Jul 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with proline at codon 678 of the TFR2 protein (p.Arg678Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with hereditary hemochromatosis (PMID: 23600741, 26408288). ClinVar contains an entry for this variant (Variation ID: 188153). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;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;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.75		Loss of MoRF binding (P = 0.0043);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204108; hg19: chr7-100224489;