chr19-2251248-A-G

Position:

chr19-2251248-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000479.5(AMH):c.974A>G(p.Gln325Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00319 in 1,503,446 control chromosomes in the GnomAD database, including 65 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 20 hom., cov: 34)

Exomes 𝑓: 0.0025 ( 45 hom. )

Consequence

AMH
NM_000479.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.65

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:

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=0.0093874335).

BP6

Variant 19-2251248-A-G is Benign according to our data. Variant chr19-2251248-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 381531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00912 (1385/151862) while in subpopulation AFR AF= 0.0244 (1010/41422). AF 95% confidence interval is 0.0231. There are 20 homozygotes in gnomad4. There are 656 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMH	NM_000479.5 linkuse as main transcript	c.974A>G	p.Gln325Arg	missense_variant	5/5	ENST00000221496.5	NP_000470.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMH	ENST00000221496.5 linkuse as main transcript	c.974A>G	p.Gln325Arg	missense_variant	5/5	1	NM_000479.5	ENSP00000221496	P1
AMH	ENST00000589313.2 linkuse as main transcript	n.1327A>G		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes

AF:

0.00908

AC:

1378

AN:

151752

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.0430

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.0323

Gnomad NFE

AF:

0.00138

Gnomad OTH

AF:

0.0149

GnomAD3 exomes

AF:

0.00467

AC:

480

AN:

102682

Hom.:

AF XY:

0.00450

AC XY:

258

AN XY:

57346

show subpopulations

Gnomad AFR exome

AF:

0.0132

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.0401

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00204

Gnomad OTH exome

AF:

0.00741

GnomAD4 exome

AF:

0.00253

AC:

3418

AN:

1351584

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

1716

AN XY:

666604

show subpopulations

Gnomad4 AFR exome

AF:

0.0233

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.0435

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.0000299

Gnomad4 NFE exome

AF:

0.000976

Gnomad4 OTH exome

AF:

0.00706

GnomAD4 genome

AF:

0.00912

AC:

1385

AN:

151862

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

656

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0244

Gnomad4 AMR

AF:

0.00511

Gnomad4 ASJ

AF:

0.0430

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.000190

Gnomad4 NFE

AF:

0.00138

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00996

Hom.:

Bravo

AF:

0.0102

ExAC

AF:

0.00459

AC:

Asia WGS

AF:

0.00291

AC:

AN:

3450

ClinVar

Significance: Benign/Likely 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	Genetic Services Laboratory, University of Chicago	Jul 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 1000Genomes: 22/2178=1% -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	AMH: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Persistent Mullerian duct syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.66

DEOGEN2

Uncertain

0.49

Eigen

Benign

0.10

Eigen_PC

Benign

0.082

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0094

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.42

Sift

Benign

0.83

Sift4G

Uncertain

0.054

Polyphen

0.95

Vest4

0.70

MVP

0.84

MPC

1.8

ClinPred

0.027

GERP RS

4.1

Varity_R

0.12

gMVP

0.30

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

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