19-2249357-C-T

Variant names:

• chr19-2249357-C-T
• rs1179977361
• NM_000479.5:c.25C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000479.5(AMH):​c.25C>T​(p.Leu9Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000049 in 1,427,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: AMH NM_000479.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.759
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• persistent Mullerian duct syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=0.759 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000479.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMH	NM_000479.5	MANE Select	c.25C>T	p.Leu9Leu	synonymous	Exon 1 of 5	NP_000470.3	P03971

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMH	ENST00000221496.5	TSL:1 MANE Select	c.25C>T	p.Leu9Leu	synonymous	Exon 1 of 5	ENSP00000221496.2	P03971
	AMH	ENST00000592877.1	TSL:3	n.49C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 194426 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000490 AC: 7 AN: 1427556 Hom.: 0 Cov.: 30 AF XY: 0.00000565 AC XY: 4 AN XY: 707476

African (AFR) AF: 0.00 AC: 0 AN: 32678

American (AMR) AF: 0.00 AC: 0 AN: 40518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37770

South Asian (SAS) AF: 0.00 AC: 0 AN: 81854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1096218

Other (OTH) AF: 0.0000507 AC: 3 AN: 59194

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.65
PhyloP100		0.76
PromoterAI		0.0012	Neutral

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: rs1179977361; hg19: chr19-2249356;