rs140765565

chr19-2251248-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 11/19 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.65

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMH	NM_000479.5	c.974A>G	p.Gln325Arg	missense_variant	5/5	ENST00000221496.5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00908 AC: 1378 AN: 151752 Hom.: 20 Cov.: 34

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.: 10 AF XY: 0.00450 AC XY: 258 AN XY: 57346

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.: 45 Cov.: 34 AF XY: 0.00257 AC XY: 1716 AN XY: 666604

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.: 20 Cov.: 34 AF XY: 0.00883 AC XY: 656 AN XY: 74264

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.: 9

Bravo AF: 0.0102

ExAC AF: 0.00459 AC: 92

Asia WGS AF: 0.00291 AC: 10 AN: 3450

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
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% -

not provided Benign:2

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	Invitae	Oct 06, 2023	- -

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	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Benign	0.66
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.42
Sift	Benign	0.83	T
Sift4G	Uncertain	0.054	T
Polyphen		0.95	P
Vest4		0.70
MVP		0.84
MPC		1.8
ClinPred		0.027	T
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

Other links and lift over

dbSNP: rs140765565; hg19: chr19-2251247; COSMIC: COSV55555353; COSMIC: COSV55555353;