19-2250659-G-A

Position:

• chr19-2250659-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000221496.5(AMH):​c.563G>A​(p.Cys188Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000433 in 1,386,916 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: AMH ENST00000221496.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.67

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-2250659-G-A is Pathogenic according to our data. Variant chr19-2250659-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 987678.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMH	NM_000479.5	c.563G>A	p.Cys188Tyr	missense_variant	3/5	ENST00000221496.5	NP_000470.3
MIR4321	NR_036207.1	n.21G>A		non_coding_transcript_exon_variant	1/1
MIR4321	unassigned_transcript_3190	n.-29G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMH	ENST00000221496.5	c.563G>A	p.Cys188Tyr	missense_variant	3/5	1	NM_000479.5	ENSP00000221496.2
AMH	ENST00000589313.2	n.916G>A		non_coding_transcript_exon_variant	1/3	5
MIR4321	ENST00000592276.1	n.21G>A		non_coding_transcript_exon_variant	1/1	6
AMH	ENST00000592877.1	n.444G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000433 AC: 6 AN: 1386916 Hom.: 0 Cov.: 35 AF XY: 0.00000438 AC XY: 3 AN XY: 684476

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Persistent Mullerian duct syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Pediatric Endocrinology Clinic, Ege University School of Medicine

-

We report two brothers. Both of them were admitted with unpalpabl testis, undetectable AMH levels, and presence of uterus in USG. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Pathogenic	0.92	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.92		Gain of phosphorylation at C188 (P = 0.0805);
MVP		0.89
MPC		0.0025
ClinPred		0.97	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.93

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

Other links and lift over

dbSNP: rs2025018868; hg19: chr19-2250658;