Variant chr1-50418957-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032110.3(DMRTA2):c.1337G>C(p.Ser446Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000769 in 1,299,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

DMRTA2
NM_032110.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.43

Variant links:

Genes affected

DMRTA2 (HGNC:13908): (DMRT like family A2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II and sex differentiation. Predicted to act upstream of or within nervous system development and skeletal muscle cell differentiation. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DMRTA2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054822177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRTA2	NM_032110.3 link	c.1337G>C	p.Ser446Thr	missense_variant	3/3	ENST00000404795.4	NP_115486.1	Q96SC8
DMRTA2	XM_011541937.3 link	c.1337G>C	p.Ser446Thr	missense_variant	2/2		XP_011540239.1	Q96SC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRTA2	ENST00000404795.4 link	c.1337G>C	p.Ser446Thr	missense_variant	3/3	5	NM_032110.3	ENSP00000383909.3		Q96SC8
DMRTA2	ENST00000418121.5 link	c.1337G>C	p.Ser446Thr	missense_variant	2/2	1		ENSP00000399370.1		Q96SC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000769

AC:

AN:

1299612

Hom.:

Cov.:

AF XY:

0.00000625

AC XY:

AN XY:

640414

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000962

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2022

The c.1337G>C (p.S446T) alteration is located in exon 3 (coding exon 2) of the DMRTA2 gene. This alteration results from a G to C substitution at nucleotide position 1337, causing the serine (S) at amino acid position 446 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0072

T;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.64

.;T

M_CAP

Benign

0.071

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.52

N;N

REVEL

Benign

0.074

Sift

Benign

0.55

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0050

B;B

Vest4

0.079

MutPred

0.21

Loss of stability (P = 0.0893);Loss of stability (P = 0.0893);

MVP

0.048

ClinPred

0.33

GERP RS

3.2

Varity_R

0.14

gMVP

0.37

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