1-50418799-G-A

Position:

• chr1-50418799-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032110.3(DMRTA2):​c.1495C>T​(p.Pro499Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DMRTA2 NM_032110.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRTA2	NM_032110.3	c.1495C>T	p.Pro499Ser	missense_variant	3/3	ENST00000404795.4	NP_115486.1
DMRTA2	XM_011541937.3	c.1495C>T	p.Pro499Ser	missense_variant	2/2		XP_011540239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRTA2	ENST00000404795.4	c.1495C>T	p.Pro499Ser	missense_variant	3/3	5	NM_032110.3	ENSP00000383909.3
DMRTA2	ENST00000418121.5	c.1495C>T	p.Pro499Ser	missense_variant	2/2	1		ENSP00000399370.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435904 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 713626

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.1495C>T (p.P499S) alteration is located in exon 3 (coding exon 2) of the DMRTA2 gene. This alteration results from a C to T substitution at nucleotide position 1495, causing the proline (P) at amino acid position 499 to be replaced by a serine (S). 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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;D
Vest4		0.58
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0507);Gain of relative solvent accessibility (P = 0.0507);
MVP		0.35
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.37
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-50884471;