chr19-2249478-G-T

Position:

chr19-2249478-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000479.5(AMH):c.146G>T(p.Ser49Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.806 in 1,605,572 control chromosomes in the GnomAD database, including 526,100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 43092 hom., cov: 33)

Exomes 𝑓: 0.81 ( 483008 hom. )

Consequence

AMH
NM_000479.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.47

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=1.3219537E-6).

BP6

Variant 19-2249478-G-T is Benign according to our data. Variant chr19-2249478-G-T is described in ClinVar as [Benign]. Clinvar id is 518296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-2249478-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMH	NM_000479.5 linkuse as main transcript	c.146G>T	p.Ser49Ile	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.146G>T	p.Ser49Ile	missense_variant	1/5	1	NM_000479.5	P1
AMH	ENST00000592877.1 linkuse as main transcript	n.170G>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.744

AC:

113039

AN:

152032

Hom.:

43095

Cov.:

show subpopulations

Gnomad AFR

AF:

0.575

Gnomad AMI

AF:

0.788

Gnomad AMR

AF:

0.749

Gnomad ASJ

AF:

0.877

Gnomad EAS

AF:

0.611

Gnomad SAS

AF:

0.786

Gnomad FIN

AF:

0.805

Gnomad MID

AF:

0.774

Gnomad NFE

AF:

0.833

Gnomad OTH

AF:

0.779

GnomAD3 exomes

AF:

0.766

AC:

180811

AN:

236156

Hom.:

70407

AF XY:

0.777

AC XY:

100103

AN XY:

128794

show subpopulations

Gnomad AFR exome

AF:

0.565

Gnomad AMR exome

AF:

0.655

Gnomad ASJ exome

AF:

0.862

Gnomad EAS exome

AF:

0.607

Gnomad SAS exome

AF:

0.778

Gnomad FIN exome

AF:

0.796

Gnomad NFE exome

AF:

0.834

Gnomad OTH exome

AF:

0.809

GnomAD4 exome

AF:

0.812

AC:

1180890

AN:

1453422

Hom.:

483008

Cov.:

AF XY:

0.813

AC XY:

587377

AN XY:

722700

show subpopulations

Gnomad4 AFR exome

AF:

0.560

Gnomad4 AMR exome

AF:

0.669

Gnomad4 ASJ exome

AF:

0.866

Gnomad4 EAS exome

AF:

0.630

Gnomad4 SAS exome

AF:

0.777

Gnomad4 FIN exome

AF:

0.798

Gnomad4 NFE exome

AF:

0.835

Gnomad4 OTH exome

AF:

0.798

GnomAD4 genome

AF:

0.743

AC:

113069

AN:

152150

Hom.:

43092

Cov.:

AF XY:

0.743

AC XY:

55277

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.575

Gnomad4 AMR

AF:

0.749

Gnomad4 ASJ

AF:

0.877

Gnomad4 EAS

AF:

0.612

Gnomad4 SAS

AF:

0.785

Gnomad4 FIN

AF:

0.805

Gnomad4 NFE

AF:

0.833

Gnomad4 OTH

AF:

0.773

Alfa

AF:

0.815

Hom.:

93875

Bravo

AF:

0.727

TwinsUK

AF:

0.839

AC:

3110

ALSPAC

AF:

0.837

AC:

3224

ESP6500AA

AF:

0.561

AC:

2464

ESP6500EA

AF:

0.831

AC:

7140

ExAC

AF:

0.759

AC:

91485

Asia WGS

AF:

0.648

AC:

2255

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Persistent Mullerian duct syndrome

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 16, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0000013

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.1

REVEL

Benign

0.24

Sift

Benign

0.041

Sift4G

Uncertain

0.018

Polyphen

0.84

Vest4

0.065

MPC

0.0016

ClinPred

0.012

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.081

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