chr19-2249385-C-T

Position:

• chr19-2249385-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000479.5(AMH):​c.53C>T​(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,588,802 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: AMH NM_000479.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.136

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008812398).
• BP6: Variant 19-2249385-C-T is Benign according to our data. Variant chr19-2249385-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1545053.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (158/152256) while in subpopulation NFE AF= 0.00163 (111/67982). AF 95% confidence interval is 0.00139. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMH	NM_000479.5	c.53C>T	p.Ala18Val	missense_variant	1/5	ENST00000221496.5	NP_000470.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMH	ENST00000221496.5	c.53C>T	p.Ala18Val	missense_variant	1/5	1	NM_000479.5	ENSP00000221496	P1
AMH	ENST00000592877.1	n.77C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00101 AC: 208 AN: 206108 Hom.: 0 AF XY: 0.00101 AC XY: 113 AN XY: 112066

Gnomad AFR exome AF: 0.000417

Gnomad AMR exome AF: 0.0000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000379

Gnomad FIN exome AF: 0.00145

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.000757

GnomAD4 exome AF: 0.00144 AC: 2069 AN: 1436546 Hom.: 2 Cov.: 30 AF XY: 0.00139 AC XY: 992 AN XY: 712534

Gnomad4 AFR exome AF: 0.000213

Gnomad4 AMR exome AF: 0.0000481

Gnomad4 ASJ exome AF: 0.0000780

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000725

Gnomad4 FIN exome AF: 0.00195

Gnomad4 NFE exome AF: 0.00174

Gnomad4 OTH exome AF: 0.000706

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.00102 AC XY: 76 AN XY: 74454

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000816 Hom.: 0

Bravo AF: 0.000960

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.00111 AC: 134

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.16
Sift	Benign	0.030	D
Sift4G	Uncertain	0.023	D
Polyphen		0.58	P
Vest4		0.16
MVP		0.80
MPC		0.0017
ClinPred		0.010	T
GERP RS		2.0
Varity_R		0.047
gMVP		0.52

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: rs61736578; hg19: chr19-2249384; COSMIC: COSV99678123; COSMIC: COSV99678123;