chr22-37066133-C-T

Position:

chr22-37066133-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001374504.1(TMPRSS6):c.2356G>A(p.Val786Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0101 in 1,613,366 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0083 ( 4 hom., cov: 33)

Exomes 𝑓: 0.010 ( 96 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 6.05

Variant links:

Genes affected

TMPRSS6 (HGNC:16517): (transmembrane serine protease 6) The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017411858).

BP6

Variant 22-37066133-C-T is Benign according to our data. Variant chr22-37066133-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr22-37066133-C-T is described in Lovd as [Likely_benign]. Variant chr22-37066133-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00829 (1262/152222) while in subpopulation NFE AF= 0.01 (680/67978). AF 95% confidence interval is 0.00938. There are 4 homozygotes in gnomad4. There are 627 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 linkuse as main transcript	c.2356G>A	p.Val786Ile	missense_variant	18/18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1 linkuse as main transcript	c.2356G>A	p.Val786Ile	missense_variant	18/18		NM_001374504.1	ENSP00000501573	P1	Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.00830

AC:

1263

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00805

AC:

2008

AN:

249464

Hom.:

AF XY:

0.00799

AC XY:

1081

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.00833

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00518

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.0177

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.00801

GnomAD4 exome

AF:

0.0103

AC:

15005

AN:

1461144

Hom.:

Cov.:

AF XY:

0.00982

AC XY:

7138

AN XY:

726864

show subpopulations

Gnomad4 AFR exome

AF:

0.00747

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.00589

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.00758

GnomAD4 genome

AF:

0.00829

AC:

1262

AN:

152222

Hom.:

Cov.:

AF XY:

0.00842

AC XY:

627

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00768

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0200

Gnomad4 NFE

AF:

0.0100

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00898

Hom.:

Bravo

AF:

0.00758

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0112

AC:

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.00954

AC:

ExAC

AF:

0.00850

AC:

1032

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00829

EpiControl

AF:

0.00990

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TMPRSS6: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2019	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2023	BS1, BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Microcytic anemia

Benign:1

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;.;.

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

T;D;T;.

MetaRNN

Benign

0.017

T;T;T;T

MetaSVM

Uncertain

0.58

MutationAssessor

Benign

1.2

L;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.64

N;N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.050

D;D;D;D

Sift4G

Benign

0.11

T;T;T;T

Polyphen

1.0

D;D;.;D

Vest4

0.29

MVP

0.95

MPC

0.60

ClinPred

0.013

GERP RS

4.5

Varity_R

0.13

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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