rs80338879

Variant names:

• chr7-100633515-A-T
• rs80338879
• NM_003227.4:c.515T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001206855.3(TFR2):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,457,080 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TFR2 NM_001206855.3 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 2.74

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 289 codons. Genomic position: 100629265. Lost 0.457 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-100633515-A-T is Pathogenic according to our data. Variant chr7-100633515-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 5382.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-100633515-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TFR2	NM_003227.4	c.515T>A	p.Met172Lys	missense_variant	Exon 4 of 18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3	c.2T>A	p.Met1?	start_lost	Exon 1 of 15		NP_001193784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8	c.515T>A	p.Met172Lys	missense_variant	Exon 4 of 18	1	NM_003227.4	ENSP00000223051.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000835 AC: 2 AN: 239618 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1457080 Hom.: 0 Cov.: 33 AF XY: 0.00000690 AC XY: 5 AN XY: 725102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemochromatosis type 3 Pathogenic:2 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TFR2 c.515T>A (p.Met172Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.3e-06 in 239618 control chromosomes (gnomAD). c.515T>A has been reported in the literature in individuals affected with Hemochromatosis Type 3 (e.g. Roetto_2001, Majore_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in retention in the ER (Wallace_2008). The following publications have been ascertained in the context of this evaluation (PMID: 11313241, 16923517, 18094142). ClinVar contains an entry for this variant (Variation ID: 5382). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 01, 2001

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	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.71	T;T;.
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.4	M;.;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.36	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.10	T;D;T
Polyphen		0.17	B;.;B
Vest4		0.82
MutPred		0.83		Gain of ubiquitination at M172 (P = 0.0146);Gain of ubiquitination at M172 (P = 0.0146);Gain of ubiquitination at M172 (P = 0.0146);
MVP		0.77
MPC		0.59
ClinPred		0.40	T
GERP RS		3.9
Varity_R		0.41
gMVP		0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs80338879; hg19: chr7-100231138;