rs41302357

chr7-100641038-G-Achr7-100641038-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_003227.4(TFR2):c.224C>T(p.Ala75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,601,638 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A75A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: TFR2 NM_003227.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 0.702

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0066734552).
• BP6: Variant 7-100641038-G-A is Benign according to our data. Variant chr7-100641038-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21373.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_benign=1}. Variant chr7-100641038-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000223 (34/152210) while in subpopulation EAS AF= 0.00601 (31/5158). AF 95% confidence interval is 0.00435. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TFR2	NM_003227.4	c.224C>T	p.Ala75Val	missense_variant	2/18	ENST00000223051.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TFR2	ENST00000223051.8	c.224C>T	p.Ala75Val	missense_variant	2/18	1	NM_003227.4	P1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152092 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00600

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000433 AC: 104 AN: 240090 Hom.: 0 AF XY: 0.000415 AC XY: 54 AN XY: 130130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00522

Gnomad SAS exome AF: 0.0000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000553

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000311 AC: 451 AN: 1449428 Hom.: 1 Cov.: 31 AF XY: 0.000307 AC XY: 221 AN XY: 719602

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.0000230

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00982

Gnomad4 SAS exome AF: 0.0000825

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000371

Gnomad4 OTH exome AF: 0.000184

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152210 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74414

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00601

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000587 Hom.: 0

Bravo AF: 0.000219

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hemochromatosis type 3 Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
not provided, no classification provided	literature only	GeneReviews	-	- -

Hereditary hemochromatosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.066	T;.;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T;.
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	0.54	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.62	N;N;N
REVEL	Benign	0.057
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.67	T;D;T
Polyphen		0.89	P;.;P
Vest4		0.20
MVP		0.67
MPC		0.33
ClinPred		0.080	T
GERP RS		3.6
Varity_R		0.16
gMVP		0.44

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: rs41302357; hg19: chr7-100238661;