12-53424458-G-A

Position:

• chr12-53424458-G-A

Variant summary

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

The NM_020547.3(AMHR2):​c.220G>A​(p.Val74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,902 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AMHR2 NM_020547.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

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]

ACMG classification

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	c.220G>A	p.Val74Met	missense_variant	2/11	ENST00000257863.9	NP_065434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMHR2	ENST00000257863.9	c.220G>A	p.Val74Met	missense_variant	2/11	1	NM_020547.3	ENSP00000257863.3
AMHR2	ENST00000379791.7	c.220G>A	p.Val74Met	missense_variant	2/9	1		ENSP00000369117.3
AMHR2	ENST00000550311.5	c.220G>A	p.Val74Met	missense_variant	2/11	1		ENSP00000446661.1
AMHR2	ENST00000553037.1	n.181G>A		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249230 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000878

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460902 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726702

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 08, 2024

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 74 of the AMHR2 protein (p.Val74Met). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of persistent Mullerian duct syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AMHR2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.0	L;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.95	P;.;.
Vest4		0.53
MutPred		0.49		Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);Gain of disorder (P = 0.0319);
MVP		0.95
MPC		0.44
ClinPred		0.75	D
GERP RS		3.0
Varity_R		0.17
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1453602766; hg19: chr12-53818242;