19-2250712-G-C

Position:

chr19-2250712-G-C

Variant summary

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

The NM_000479.5(AMH):c.616G>C(p.Ala206Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,538,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

AMH
NM_000479.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.52

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 links:

MIR4321 (HGNC:38244): (microRNA 4321) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4321 links:

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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
AMH	NM_000479.5 linkuse as main transcript	c.616G>C	p.Ala206Pro	missense_variant	3/5	ENST00000221496.5	NP_000470.3
MIR4321	NR_036207.1 linkuse as main transcript	n.74G>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
AMH	ENST00000221496.5 linkuse as main transcript	c.616G>C	p.Ala206Pro	missense_variant	3/5	1	NM_000479.5	ENSP00000221496	P1
MIR4321	ENST00000592276.1 linkuse as main transcript	n.74G>C		non_coding_transcript_exon_variant	1/1
AMH	ENST00000589313.2 linkuse as main transcript	n.969G>C		non_coding_transcript_exon_variant	1/3	5
AMH	ENST00000592877.1 linkuse as main transcript	n.497G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000361

AC:

AN:

1386312

Hom.:

Cov.:

AF XY:

0.00000438

AC XY:

AN XY:

684464

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2016

The A206P variant in the AMH gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A206P variant was not observed (average read depth 3.0) in approximately 5600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A206P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A206P as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.67

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.48

Sift

Benign

0.058

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.24

MutPred

0.73

Loss of catalytic residue at A206 (P = 0.0135);

MVP

0.87

MPC

0.0034

ClinPred

0.80

GERP RS

4.2

Varity_R

0.34

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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