12-53424293-C-G

Variant names:

• chr12-53424293-C-G
• rs756301317
• NM_020547.3:c.55C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_020547.3(AMHR2):​c.55C>G​(p.Pro19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,460,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: AMHR2 NM_020547.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.233
• Publications: 2 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 0 ACMG points.

• PP5: Variant 12-53424293-C-G is Pathogenic according to our data. Variant chr12-53424293-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1256033.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.082761824). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMHR2	NM_020547.3	c.55C>G	p.Pro19Ala	missense_variant	Exon 2 of 11	ENST00000257863.9	NP_065434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMHR2	ENST00000257863.9	c.55C>G	p.Pro19Ala	missense_variant	Exon 2 of 11	1	NM_020547.3	ENSP00000257863.3
AMHR2	ENST00000379791.7	c.55C>G	p.Pro19Ala	missense_variant	Exon 2 of 9	1		ENSP00000369117.3
AMHR2	ENST00000550311.5	c.55C>G	p.Pro19Ala	missense_variant	Exon 2 of 11	1		ENSP00000446661.1
AMHR2	ENST00000553037.1	n.16C>G		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251376 AF XY: 0.0000662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1460162 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 726386

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000630 AC: 25 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4364

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Genetic non-acquired premature ovarian failure Pathogenic:1

Oct 01, 2019

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.36	T;.;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.34	N;N;N
PhyloP100		0.23
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.13	T;D;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.41
MutPred		0.24		Gain of catalytic residue at P19 (P = 0.0193);Gain of catalytic residue at P19 (P = 0.0193);Gain of catalytic residue at P19 (P = 0.0193);
MVP		0.97
MPC		0.28
ClinPred		0.17	T
GERP RS		4.5
PromoterAI		0.0018	Neutral
Varity_R		0.099
gMVP		0.26
Mutation Taster		=67/33	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

dbSNP: rs756301317; hg19: chr12-53818077;