12-53424408-A-G

Position:

chr12-53424408-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020547.3(AMHR2):c.170A>G(p.Tyr57Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

AMHR2
NM_020547.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Variant links:

Genes affected

AMHR2 (HGNC:465): (anti-Mullerian hormone receptor type 2) This gene encodes the receptor for the anti-Mullerian hormone (AMH) which, in addition to testosterone, results in male sex differentiation. AMH and testosterone are produced in the testes by different cells and have different effects. Testosterone promotes the development of male genitalia while the binding of AMH to the encoded receptor prevents the development of the mullerian ducts into uterus and Fallopian tubes. Mutations in this gene are associated with persistent Mullerian duct syndrome type II. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Sep 2009]

AMHR2 links:

AMHR2 (HGNC:):

AMHR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMHR2	NM_020547.3 linkuse as main transcript	c.170A>G	p.Tyr57Cys	missense_variant	2/11	ENST00000257863.9	NP_065434.1	Q16671-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AMHR2	ENST00000257863.9 linkuse as main transcript	c.170A>G	p.Tyr57Cys	missense_variant	2/11	1	NM_020547.3	ENSP00000257863.3	Q16671-1
AMHR2	ENST00000379791.7 linkuse as main transcript	c.170A>G	p.Tyr57Cys	missense_variant	2/9	1		ENSP00000369117.3	Q16671-3
AMHR2	ENST00000550311.5 linkuse as main transcript	c.170A>G	p.Tyr57Cys	missense_variant	2/11	1		ENSP00000446661.1	Q16671-2
AMHR2	ENST00000553037.1 linkuse as main transcript	n.131A>G		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250334

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135434

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 01, 2020

DNA sequence analysis of the AMHR2 gene demonstrated a sequence change, c.170A>G, in exon 2 that results in an amino acid change, p.Tyr57Cys. This sequence change does not appear to have been previously described in patients with AMHR2-related disorders and has been described in the gnomAD database with a low population frequency of 0.0016% (dbSNP rs574868905). The p.Tyr57Cys change affects a highly conserved amino acid residue located in a domain of the AMHR2 protein that is known to be functional. The p.Tyr57Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these evidences and the lack of functional studies, the clinical significance of the p.Tyr57Cys change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.;.

Eigen

Benign

0.090

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.86

D;T;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

1.0

L;L;L

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Pathogenic

0.66

Sift

Benign

0.070

T;T;D

Sift4G

Benign

0.17

T;D;D

Polyphen

0.90

P;.;.

Vest4

0.72

MutPred

0.51

Gain of catalytic residue at L56 (P = 8e-04);Gain of catalytic residue at L56 (P = 8e-04);Gain of catalytic residue at L56 (P = 8e-04);

MVP

0.97

MPC

0.54

ClinPred

0.33

GERP RS

3.0

Varity_R

0.19

gMVP

0.44

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