rs80338879

chr7-100633515-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1 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 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	UniProt
TFR2	NM_003227.4	c.515T>A	p.Met172Lys	missense_variant	4/18	ENST00000223051.8
TFR2	NM_001206855.3	c.2T>A	p.Met1?	start_lost	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.515T>A	p.Met172Lys	missense_variant	4/18	1	NM_003227.4	P1

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:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hemochromatosis type 3 Pathogenic:1 Other:1

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

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
MutationTaster	Benign	0.66	A;A;A
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;