19-2251248-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

persistent Mullerian duct syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

AMH 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=0.0093874335).

BP6

Variant 19-2251248-A-G is Benign according to our data. Variant chr19-2251248-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMH	NM_000479.5 link	c.974A>G	p.Gln325Arg	missense_variant	Exon 5 of 5	ENST00000221496.5	NP_000470.3	P03971

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMH	ENST00000221496.5 link	c.974A>G	p.Gln325Arg	missense_variant	Exon 5 of 5	1	NM_000479.5	ENSP00000221496.2		P03971
AMH	ENST00000589313.2 link	n.1327A>G		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes

AF:

0.00467

AC:

480

AN:

102682

AF XY:

0.00450

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 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

African (AFR)

AF:

0.0233

AC:

643

AN:

27546

American (AMR)

AF:

0.00300

AC:

AN:

32336

Ashkenazi Jewish (ASJ)

AF:

0.0435

AC:

1045

AN:

24016

East Asian (EAS)

AF:

0.00

AC:

AN:

32086

South Asian (SAS)

AF:

0.00125

AC:

AN:

75760

European-Finnish (FIN)

AF:

0.0000299

AC:

AN:

33498

Middle Eastern (MID)

AF:

0.0245

AC:

AN:

4034

European-Non Finnish (NFE)

AF:

0.000976

AC:

1041

AN:

1066100

Other (OTH)

AF:

0.00706

AC:

397

AN:

56208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

198

396

595

793

991

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00912

AC:

1385

AN:

151862

Hom.:

Cov.:

AF XY:

0.00883

AC XY:

656

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.0244

AC:

1010

AN:

41422

American (AMR)

AF:

0.00511

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0430

AC:

149

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00228

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.0347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00138

AC:

AN:

67898

Other (OTH)

AF:

0.0147

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

129

193

258

322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00996

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

Nov 01, 2015

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely 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 1000Genomes: 22/2178=1% -

Jul 14, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AMH: BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Persistent Mullerian duct syndrome

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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

PhyloP100

3.6

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

Mutation Taster

=82/18

polymorphism

(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