22-37066896-A-G

Position:

chr22-37066896-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374504.1(TMPRSS6):c.2180T>C(p.Val727Ala) variant causes a missense change. The variant allele was found at a frequency of 0.57 in 1,613,526 control chromosomes in the GnomAD database, including 267,184 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.64 ( 32125 hom., cov: 33)

Exomes 𝑓: 0.56 ( 235059 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.84

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.892132E-6).

BP6

Variant 22-37066896-A-G is Benign according to our data. Variant chr22-37066896-A-G is described in ClinVar as [Benign]. Clinvar id is 262725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37066896-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1 linkuse as main transcript	c.2180T>C	p.Val727Ala	missense_variant	17/18	ENST00000676104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS6	ENST00000676104.1 linkuse as main transcript	c.2180T>C	p.Val727Ala	missense_variant	17/18		NM_001374504.1	P1	Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.635

AC:

96440

AN:

151832

Hom.:

32071

Cov.:

show subpopulations

Gnomad AFR

AF:

0.846

Gnomad AMI

AF:

0.581

Gnomad AMR

AF:

0.517

Gnomad ASJ

AF:

0.563

Gnomad EAS

AF:

0.445

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.652

Gnomad MID

AF:

0.592

Gnomad NFE

AF:

0.564

Gnomad OTH

AF:

0.592

GnomAD3 exomes

AF:

0.566

AC:

141752

AN:

250414

Hom.:

41207

AF XY:

0.558

AC XY:

75649

AN XY:

135524

show subpopulations

Gnomad AFR exome

AF:

0.859

Gnomad AMR exome

AF:

0.525

Gnomad ASJ exome

AF:

0.544

Gnomad EAS exome

AF:

0.450

Gnomad SAS exome

AF:

0.478

Gnomad FIN exome

AF:

0.658

Gnomad NFE exome

AF:

0.564

Gnomad OTH exome

AF:

0.558

GnomAD4 exome

AF:

0.563

AC:

823260

AN:

1461576

Hom.:

235059

Cov.:

AF XY:

0.560

AC XY:

407285

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.865

Gnomad4 AMR exome

AF:

0.520

Gnomad4 ASJ exome

AF:

0.540

Gnomad4 EAS exome

AF:

0.444

Gnomad4 SAS exome

AF:

0.480

Gnomad4 FIN exome

AF:

0.655

Gnomad4 NFE exome

AF:

0.562

Gnomad4 OTH exome

AF:

0.571

GnomAD4 genome

AF:

0.635

AC:

96540

AN:

151950

Hom.:

32125

Cov.:

AF XY:

0.631

AC XY:

46824

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.846

Gnomad4 AMR

AF:

0.516

Gnomad4 ASJ

AF:

0.563

Gnomad4 EAS

AF:

0.446

Gnomad4 SAS

AF:

0.461

Gnomad4 FIN

AF:

0.652

Gnomad4 NFE

AF:

0.564

Gnomad4 OTH

AF:

0.586

Alfa

AF:

0.565

Hom.:

50258

Bravo

AF:

0.639

TwinsUK

AF:

0.553

AC:

2051

ALSPAC

AF:

0.540

AC:

2081

ESP6500AA

AF:

0.842

AC:

3708

ESP6500EA

AF:

0.565

AC:

4858

ExAC

AF:

0.572

AC:

69384

EpiCase

AF:

0.571

EpiControl

AF:

0.557

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 25312922, 22265928, 25601433, 23293981, 20738301, 24661031, 21873547, 23433094, 22885719, 21785125, 19820698, 23222517, 23144979, 19820699, 27346686, 28447549, 30963028, 31640930, 25557470) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Microcytic anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Iron-refractory iron deficiency anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.096

LIST_S2

Benign

0.017

T;T;T;.

MetaRNN

Benign

0.0000039

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.0

N;.;.;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.26

N;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

0.73

T;T;T;T

Polyphen

0.0

B;B;.;B

Vest4

0.038

MPC

0.19

ClinPred

0.0046

GERP RS

4.7

Varity_R

0.068

gMVP

0.28

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