chr2-219575194-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002191.4(INHA):c.769G>A(p.Ala257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,614,244 control chromosomes in the GnomAD database, including 673 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 34 hom., cov: 33)

Exomes 𝑓: 0.025 ( 639 hom. )

Consequence

INHA
NM_002191.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.103

Publications

35 publications found

Variant links:

Genes affected

INHA (HGNC:6065): (inhibin subunit alpha) This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate multiple peptide products, including the alpha subunit of the inhibin A and B protein complexes. These complexes negatively regulate follicle stimulating hormone secretion from the pituitary gland. Inhibins have also been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. Mutations in this gene may be associated with male infertility and premature ovarian failure in female human patients. [provided by RefSeq, Aug 2016]

INHA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025029778).

BP6

Variant 2-219575194-G-A is Benign according to our data. Variant chr2-219575194-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INHA	NM_002191.4 link	c.769G>A	p.Ala257Thr	missense_variant	Exon 2 of 2	ENST00000243786.3	NP_002182.1	P05111

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INHA	ENST00000243786.3 link	c.769G>A	p.Ala257Thr	missense_variant	Exon 2 of 2	1	NM_002191.4	ENSP00000243786.2		P05111
INHA	ENST00000489456.1 link	n.*141G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2697

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00470

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0157

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0517

Gnomad FIN

AF:

0.0115

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0233

AC:

5867

AN:

251420

AF XY:

0.0258

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.00783

Gnomad ASJ exome

AF:

0.0469

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0132

Gnomad NFE exome

AF:

0.0253

Gnomad OTH exome

AF:

0.0251

GnomAD4 exome

AF:

0.0253

AC:

37041

AN:

1461894

Hom.:

639

Cov.:

AF XY:

0.0264

AC XY:

19234

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00367

AC:

123

AN:

33480

American (AMR)

AF:

0.00910

AC:

407

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

1272

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0556

AC:

4794

AN:

86258

European-Finnish (FIN)

AF:

0.0130

AC:

692

AN:

53420

Middle Eastern (MID)

AF:

0.0395

AC:

228

AN:

5768

European-Non Finnish (NFE)

AF:

0.0251

AC:

27923

AN:

1112012

Other (OTH)

AF:

0.0264

AC:

1596

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2660

5319

7979

10638

13298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1056

2112

3168

4224

5280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0177

AC:

2690

AN:

152350

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1308

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00469

AC:

195

AN:

41570

American (AMR)

AF:

0.0157

AC:

240

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

150

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0509

AC:

246

AN:

4832

European-Finnish (FIN)

AF:

0.0115

AC:

122

AN:

10628

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0246

AC:

1676

AN:

68036

Other (OTH)

AF:

0.0241

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

138

276

413

551

689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0226

Hom.:

Bravo

AF:

0.0174

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0251

AC:

216

ExAC

AF:

0.0236

AC:

2863

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0294

EpiControl

AF:

0.0254

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 236/13006=1.81% -

INHA-related disorder

Benign:1

Apr 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Premature ovarian failure

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Ala257Thr variant in INHA has been identified in 3 individuals with premature ovarian failure (PMID: 11098038), but has also been identified in >5% of South Asian chromosomes and 82 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for premature ovarian failure. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.0

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.6

PhyloP100

0.10

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.79

REVEL

Uncertain

0.41

Sift

Benign

0.13

Sift4G

Benign

0.23

Polyphen

0.70

Vest4

0.043

MPC

0.20

ClinPred

0.0047

GERP RS

-2.1

Varity_R

0.063

gMVP

0.54

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over