chr19-2249478-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

107 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=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 VariationId is 518296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000479.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMH	NM_000479.5	MANE Select	c.146G>T	p.Ser49Ile	missense	Exon 1 of 5	NP_000470.3	P03971

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMH	ENST00000221496.5	TSL:1 MANE Select	c.146G>T	p.Ser49Ile	missense	Exon 1 of 5	ENSP00000221496.2	P03971
	AMH	ENST00000592877.1	TSL:3	n.170G>T		non_coding_transcript_exon	Exon 1 of 2

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

GnomAD2 exomes

AF:

0.766

AC:

180811

AN:

236156

AF XY:

0.777

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 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

African (AFR)

AF:

0.560

AC:

18676

AN:

33352

American (AMR)

AF:

0.669

AC:

29291

AN:

43794

Ashkenazi Jewish (ASJ)

AF:

0.866

AC:

22507

AN:

26002

East Asian (EAS)

AF:

0.630

AC:

24827

AN:

39430

South Asian (SAS)

AF:

0.777

AC:

66233

AN:

85276

European-Finnish (FIN)

AF:

0.798

AC:

40305

AN:

50516

Middle Eastern (MID)

AF:

0.810

AC:

4660

AN:

5752

European-Non Finnish (NFE)

AF:

0.835

AC:

926426

AN:

1109214

Other (OTH)

AF:

0.798

AC:

47965

AN:

60086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

14986

29972

44958

59944

74930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20918

41836

62754

83672

104590

<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:

0.743

AC:

113069

AN:

152150

Hom.:

43092

Cov.:

AF XY:

0.743

AC XY:

55277

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.575

AC:

23855

AN:

41500

American (AMR)

AF:

0.749

AC:

11456

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.877

AC:

3046

AN:

3472

East Asian (EAS)

AF:

0.612

AC:

3161

AN:

5166

South Asian (SAS)

AF:

0.785

AC:

3787

AN:

4826

European-Finnish (FIN)

AF:

0.805

AC:

8531

AN:

10592

Middle Eastern (MID)

AF:

0.774

AC:

226

AN:

292

European-Non Finnish (NFE)

AF:

0.833

AC:

56655

AN:

67988

Other (OTH)

AF:

0.773

AC:

1633

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1449

2898

4348

5797

7246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

846

1692

2538

3384

4230

<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:

0.814

Hom.:

117642

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Persistent Mullerian duct syndrome (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

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

PhyloP100

1.5

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

PromoterAI

-0.029

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.081

gMVP

0.56

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over