19-2250676-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_ModeratePM2PP3_Moderate

The NM_000479.5(AMH):​c.580C>T​(p.Arg194Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,539,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AMH
NM_000479.5 missense

Scores

4
7
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0500
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PS1
Transcript NM_000479.5 (AMH) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AMHNM_000479.5 linkc.580C>T p.Arg194Cys missense_variant Exon 3 of 5 ENST00000221496.5 NP_000470.3 P03971
MIR4321NR_036207.1 linkn.38C>T non_coding_transcript_exon_variant Exon 1 of 1
MIR4321unassigned_transcript_3189 n.-12C>T upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AMHENST00000221496.5 linkc.580C>T p.Arg194Cys missense_variant Exon 3 of 5 1 NM_000479.5 ENSP00000221496.2 P03971
AMHENST00000589313.2 linkn.933C>T non_coding_transcript_exon_variant Exon 1 of 3 5
MIR4321ENST00000592276.1 linkn.38C>T non_coding_transcript_exon_variant Exon 1 of 1 6
AMHENST00000592877.1 linkn.461C>T non_coding_transcript_exon_variant Exon 2 of 2 3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152216
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000146
AC:
2
AN:
137028
Hom.:
0
AF XY:
0.0000268
AC XY:
2
AN XY:
74712
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000885
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
17
AN:
1387464
Hom.:
0
Cov.:
35
AF XY:
0.0000146
AC XY:
10
AN XY:
684840
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000101
Gnomad4 FIN exome
AF:
0.0000263
Gnomad4 NFE exome
AF:
0.00000741
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152216
Hom.:
0
Cov.:
34
AF XY:
0.0000269
AC XY:
2
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756
ExAC
AF:
0.0000309
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Oct 08, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. Experimental studies have shown that this missense change affects AMH function (PMID: 14673134). This missense change has been observed in individual(s) with persistent Mullerian duct syndrome (PMID: 8162013). While this variant is present in population databases (rs777003373), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with cysteine at codon 194 of the AMH protein (p.Arg194Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.89
D
Eigen
Benign
-0.40
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.24
N
LIST_S2
Benign
0.70
T
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.89
D
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
1.8
L
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-4.4
D
REVEL
Uncertain
0.57
Sift
Uncertain
0.0060
D
Sift4G
Uncertain
0.020
D
Polyphen
0.99
D
Vest4
0.46
MutPred
0.88
Loss of MoRF binding (P = 0.0222);
MVP
0.76
MPC
0.0032
ClinPred
0.80
D
GERP RS
-0.30
Varity_R
0.27
gMVP
0.62

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.

Other links and lift over

dbSNP: rs777003373; hg19: chr19-2250675; API