7-100631815-C-T

Position:

chr7-100631815-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003227.4(TFR2):c.1097G>A(p.Arg366His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,612,312 control chromosomes in the GnomAD database, including 7 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).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00046 ( 7 hom. )

Consequence

TFR2
NM_003227.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -1.55

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:

LOC124901709 (HGNC:):

LOC124901709 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008228421).

BP6

Variant 7-100631815-C-T is Benign according to our data. Variant chr7-100631815-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 530395.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TFR2	NM_003227.4 linkuse as main transcript	c.1097G>A	p.Arg366His	missense_variant	8/18	ENST00000223051.8	NP_003218.2
LOC124901709	XR_007060454.1 linkuse as main transcript	n.503+590C>T		intron_variant, non_coding_transcript_variant
TFR2	NM_001206855.3 linkuse as main transcript	c.584G>A	p.Arg195His	missense_variant	5/15		NP_001193784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TFR2	ENST00000223051.8 linkuse as main transcript	c.1097G>A	p.Arg366His	missense_variant	8/18	1	NM_003227.4	ENSP00000223051	P1	Q9UP52-1

Frequencies

GnomAD3 genomes

AF:

0.000783

AC:

119

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000578

Gnomad EAS

AF:

0.00117

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00765

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000867

AC:

217

AN:

250160

Hom.:

AF XY:

0.000755

AC XY:

102

AN XY:

135130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000603

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0000990

Gnomad FIN exome

AF:

0.00709

Gnomad NFE exome

AF:

0.000327

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.000464

AC:

678

AN:

1460282

Hom.:

Cov.:

AF XY:

0.000479

AC XY:

348

AN XY:

726186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000461

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000163

Gnomad4 FIN exome

AF:

0.00853

Gnomad4 NFE exome

AF:

0.000113

Gnomad4 OTH exome

AF:

0.000978

GnomAD4 genome

AF:

0.000783

AC:

119

AN:

152030

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000578

Gnomad4 EAS

AF:

0.00137

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00765

Gnomad4 NFE

AF:

0.000383

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000381

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000824

AC:

100

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Hemochromatosis type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary hemochromatosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.35

DANN

Benign

0.80

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.31

T;.

M_CAP

Benign

0.0039

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.060

N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.4

N;N

REVEL

Benign

0.049

Sift

Benign

0.052

T;T

Sift4G

Uncertain

0.034

D;D

Polyphen

0.0030

B;B

Vest4

0.13

MVP

0.25

MPC

0.41

ClinPred

0.032

GERP RS

-9.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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