19-2249478-G-C

Variant names:

• chr19-2249478-G-C
• rs10407022
• NM_000479.5:c.146G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000479.5(AMH):​c.146G>C​(p.Ser49Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S49I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AMH NM_000479.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19814909).

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.146G>C	p.Ser49Thr	missense	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.146G>C	p.Ser49Thr	missense	Exon 1 of 5	ENSP00000221496.2	P03971
	AMH	ENST00000592877.1	TSL:3	n.170G>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453628 Hom.: 0 Cov.: 96 AF XY: 0.00000138 AC XY: 1 AN XY: 722800

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109284

Other (OTH) AF: 0.00 AC: 0 AN: 60090

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.21
Sift	Benign	0.18	T
Sift4G	Benign	0.081	T
Polyphen		0.60	P
Vest4		0.20
MutPred		0.48		Loss of disorder (P = 0.0645)
MVP		0.72
MPC		0.0018
ClinPred		0.13	T
GERP RS		2.7
PromoterAI		-0.037	Neutral
Varity_R		0.053
gMVP		0.40
Mutation Taster		=96/4	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: rs10407022; hg19: chr19-2249477;