12-53423957-G-C

Variant names:

• chr12-53423957-G-C
• NM_020547.3:c.23G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020547.3(AMHR2):​c.23G>C​(p.Trp8Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMHR2 NM_020547.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• persistent Mullerian duct syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMHR2	NM_020547.3	c.23G>C	p.Trp8Ser	missense_variant	Exon 1 of 11	ENST00000257863.9	NP_065434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMHR2	ENST00000257863.9	c.23G>C	p.Trp8Ser	missense_variant	Exon 1 of 11	1	NM_020547.3	ENSP00000257863.3
AMHR2	ENST00000379791.7	c.23G>C	p.Trp8Ser	missense_variant	Exon 1 of 9	1		ENSP00000369117.3
AMHR2	ENST00000550311.5	c.23G>C	p.Trp8Ser	missense_variant	Exon 1 of 11	1		ENSP00000446661.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23G>C (p.W8S) alteration is located in exon 1 (coding exon 1) of the AMHR2 gene. This alteration results from a G to C substitution at nucleotide position 23, causing the tryptophan (W) at amino acid position 8 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.81	L;L;L
PhyloP100		4.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.030	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.96	D;.;.
Vest4		0.61
MutPred		0.69		Gain of catalytic residue at S4 (P = 2e-04);Gain of catalytic residue at S4 (P = 2e-04);Gain of catalytic residue at S4 (P = 2e-04);
MVP		0.98
MPC		0.33
ClinPred		0.91	D
GERP RS		4.9
PromoterAI		0.051	Neutral
Varity_R		0.34
gMVP		0.64
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

hg19: chr12-53817741;