9-1051698-G-T

Position:

chr9-1051698-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181872.6(DMRT2):c.85G>T(p.Ala29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,555,590 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DMRT2
NM_181872.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.181

Variant links:

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 links:

DMRT2 (HGNC:):

DMRT2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07047424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRT2	NM_181872.6 linkuse as main transcript	c.85G>T	p.Ala29Ser	missense_variant	2/4	ENST00000358146.7	NP_870987.2	Q9Y5R5-1Q05C20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRT2	ENST00000358146.7 linkuse as main transcript	c.85G>T	p.Ala29Ser	missense_variant	2/4	1	NM_181872.6	ENSP00000350865.2		Q9Y5R5-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000138

AC:

AN:

152504

Hom.:

AF XY:

0.000165

AC XY:

AN XY:

84978

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000394

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000289

Gnomad OTH exome

AF:

0.000240

GnomAD4 exome

AF:

0.000154

AC:

216

AN:

1403362

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

108

AN XY:

694992

show subpopulations

Gnomad4 AFR exome

AF:

0.0000330

Gnomad4 AMR exome

AF:

0.0000803

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000246

Gnomad4 NFE exome

AF:

0.000186

Gnomad4 OTH exome

AF:

0.000120

GnomAD4 genome

AF:

0.000204

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000346

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.0000451

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2024

The c.85G>T (p.A29S) alteration is located in exon 2 (coding exon 1) of the DMRT2 gene. This alteration results from a G to T substitution at nucleotide position 85, causing the alanine (A) at amino acid position 29 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

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 tolerated. 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. ClinVar contains an entry for this variant (Variation ID: 1413724). This variant has not been reported in the literature in individuals affected with DMRT2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 29 of the DMRT2 protein (p.Ala29Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.5

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

.;.;T;.;T;.

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.51

.;.;T;.;.;T

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.070

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L;L;L;L

PrimateAI

Uncertain

0.66

PROVEAN

Benign

0.030

.;N;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

0.046

.;D;T;D;T;D

Sift4G

Benign

0.59

T;T;T;T;T;T

Polyphen

0.099

.;.;B;.;B;.

Vest4

0.071

MutPred

0.068

Gain of phosphorylation at A29 (P = 0.009);Gain of phosphorylation at A29 (P = 0.009);Gain of phosphorylation at A29 (P = 0.009);Gain of phosphorylation at A29 (P = 0.009);Gain of phosphorylation at A29 (P = 0.009);Gain of phosphorylation at A29 (P = 0.009);

MVP

0.28

MPC

0.0071

ClinPred

0.045

GERP RS

1.6

Varity_R

0.061

gMVP

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over