chr19-2249367-T-G

Position:

chr19-2249367-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PS1_ModerateBP4_StrongBS1_SupportingBS2

The NM_000479.5(AMH):c.35T>G(p.Val12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,582,944 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 7 hom. )

Consequence

AMH
NM_000479.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.647

Variant links:

Genes affected

AMH (HGNC:464): (anti-Mullerian hormone) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate N- and C-terminal cleavage products that homodimerize and associate to form a biologically active noncovalent complex. This complex binds to the anti-Mullerian hormone receptor type 2 and causes the regression of Mullerian ducts in the male embryo that would otherwise differentiate into the uterus and fallopian tubes. This protein also plays a role in Leydig cell differentiation and function and follicular development in adult females. Mutations in this gene result in persistent Mullerian duct syndrome. [provided by RefSeq, Jul 2016]

AMH links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PS1

Transcript NM_000479.5 (AMH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.035728693).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00171 (261/152268) while in subpopulation NFE AF= 0.00303 (206/68002). AF 95% confidence interval is 0.00269. There are 1 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMH	NM_000479.5 linkuse as main transcript	c.35T>G	p.Val12Gly	missense_variant	1/5	ENST00000221496.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMH	ENST00000221496.5 linkuse as main transcript	c.35T>G	p.Val12Gly	missense_variant	1/5	1	NM_000479.5	P1
AMH	ENST00000592877.1 linkuse as main transcript	n.59T>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

262

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00303

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00139

AC:

276

AN:

197862

Hom.:

AF XY:

0.00134

AC XY:

144

AN XY:

107714

show subpopulations

Gnomad AFR exome

AF:

0.000352

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000664

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000388

Gnomad FIN exome

AF:

0.0000609

Gnomad NFE exome

AF:

0.00263

Gnomad OTH exome

AF:

0.00156

GnomAD4 exome

AF:

0.00290

AC:

4150

AN:

1430676

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

1990

AN XY:

709306

show subpopulations

Gnomad4 AFR exome

AF:

0.000489

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.000901

Gnomad4 EAS exome

AF:

0.0000264

Gnomad4 SAS exome

AF:

0.0000731

Gnomad4 FIN exome

AF:

0.000102

Gnomad4 NFE exome

AF:

0.00356

Gnomad4 OTH exome

AF:

0.00234

GnomAD4 genome

AF:

0.00171

AC:

261

AN:

152268

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00303

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00231

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000459

AC:

ESP6500EA

AF:

0.00280

AC:

ExAC

AF:

0.00117

AC:

141

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 12 of the AMH protein (p.Val12Gly). This variant is present in population databases (rs149082963, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of persistent M√ºllerian Duct Syndrome (PMID: 8162013, 22188863). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 381731). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Studies have shown that this missense change does not affect mRNA splicing (PMID: 37004205). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2024	Reported in the heterozygous state in female patients with polycystic ovary syndrome or with premature ovarian insufficiency in published literature, but familial segregation information and additional clinical information were not included (PMID: 28505284, 36099812); Published functional studies suggest a damaging effect with reduced AMH signaling activity (PMID: 28505284); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9302384, 23611722, 34426522, 30786001, 37004205, 28505284, 28528332, 8162013, 22188863, 36099812, 30668521) -

AMH-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2024

The AMH c.35T>G variant is predicted to result in the amino acid substitution p.Val12Gly. This variant has been reported in the compound heterozygous and homozygous states in two families with male individuals affected with persistent Mullerian duct syndrome (Imbeaud et al. 1994. PubMed ID: 8162013; Mazen et al. 2011. PubMed ID: 22188863). This variant has also been reported in the heterozygous state in female individuals with polycystic ovary syndrome (Gorsic et al. 2017. PubMed ID: 28505284). At PreventionGenetics, this variant was observed in the homozygous state in an individual with neurodevelopmental features, musculoskeletal features, dysmorphic features, gastrointestinal and genitourinary issues. Functional studies have conflicting results on the impact of this variant; a dual luciferase reporter assay showed significantly reduced AMH signaling (Gorsic et al. 2017. PubMed ID: 28505284), while another luciferase reporter assay showed comparable bioactivity to wildtype (Meng et al. 2023, PubMedID: 37004205). This variant is present in 0.35% of alleles in individuals of European (Non-Finnish) descent (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38) 8 homozygotes are documented, which is higher than expected for this disorder. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.55

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.29

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.0

MutationTaster

Benign

0.88

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.60

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0050

Polyphen

0.91

Vest4

0.74

MVP

0.68

MPC

0.0014

ClinPred

0.0097

GERP RS

1.3

Varity_R

0.095

gMVP

0.56

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