9-1051642-C-A

Position:

• chr9-1051642-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_181872.6(DMRT2):​c.29C>A​(p.Ala10Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,413,714 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (6 hom.)
• Consequence: DMRT2 NM_181872.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.969

Genes affected

DMRT2 (HGNC:2935): (doublesex and mab-3 related transcription factor 2) The protein encoded by this gene belongs to the DMRT gene family, sharing a DM DNA-binding domain with Drosophila 'doublesex' (dsx) and C. elegans mab3, genes involved in sex determination in these organisms. Also, this gene is located in a region of the human genome (chromosome 9p24.3) associated with gonadal dysgenesis and XY sex reversal. Hence this gene is one of the candidates for sex-determining gene(s) on chr 9. [provided by RefSeq, Apr 2010]

DMRT2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1252363).
• BS2: High Homozygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRT2	NM_181872.6	c.29C>A	p.Ala10Asp	missense_variant	2/4	ENST00000358146.7	NP_870987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRT2	ENST00000358146.7	c.29C>A	p.Ala10Asp	missense_variant	2/4	1	NM_181872.6	ENSP00000350865.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000290 AC: 41 AN: 1413714 Hom.: 6 Cov.: 31 AF XY: 0.0000370 AC XY: 26 AN XY: 701788

Gnomad4 AFR exome AF: 0.000788

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.000237

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 08, 2023

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 10 of the DMRT2 protein (p.Ala10Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with DMRT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2063059). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	.;.;T;.;.;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.47	.;.;T;.;T;.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L;L;.;L;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.97	.;N;N;N;N;N;N
REVEL	Benign	0.079
Sift	Uncertain	0.0010	.;D;D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;T;D;D
Polyphen		0.61	.;.;P;.;.;P;.
Vest4		0.23
MutPred		0.10		Loss of catalytic residue at A10 (P = 0.0594);Loss of catalytic residue at A10 (P = 0.0594);Loss of catalytic residue at A10 (P = 0.0594);Loss of catalytic residue at A10 (P = 0.0594);Loss of catalytic residue at A10 (P = 0.0594);Loss of catalytic residue at A10 (P = 0.0594);Loss of catalytic residue at A10 (P = 0.0594);
MVP		0.57
MPC		0.0062
ClinPred		0.32	T
GERP RS		2.0
Varity_R		0.35
gMVP		0.036

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: rs1001018184; hg19: chr9-1051642;