Variant rs80338879 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_003227.4(TFR2):c.515T>A(p.Met172Lys) variant causes a missense 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 (no stars).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 2.74

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

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 no_assertion_criteria_provided, 0 stars. Variant chr7-100633515-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TFR2	NM_003227.4 linkuse as main transcript	c.515T>A	p.Met172Lys	missense_variant	4/18	ENST00000223051.8	NP_003218.2
TFR2	NM_001206855.3 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/15		NP_001193784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 linkuse as main transcript	c.515T>A	p.Met172Lys	missense_variant	4/18	1	NM_003227.4	ENSP00000223051	P1	Q9UP52-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000835

AC:

AN:

239618

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131374

show subpopulations

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:

AN:

1457080

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

725102

show subpopulations

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.:

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hemochromatosis type 3

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.21

T;.;T

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.71

T;T;.

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

M;.;M

MutationTaster

Benign

0.66

A;A;A

PrimateAI

Uncertain

0.53

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over