chr1-50418744-G-A

Position:

• chr1-50418744-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032110.3(DMRTA2):​c.1550C>T​(p.Ala517Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,406,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A517G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DMRTA2 NM_032110.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16106796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRTA2	NM_032110.3	c.1550C>T	p.Ala517Val	missense_variant	3/3	ENST00000404795.4	NP_115486.1
DMRTA2	XM_011541937.3	c.1550C>T	p.Ala517Val	missense_variant	2/2		XP_011540239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRTA2	ENST00000404795.4	c.1550C>T	p.Ala517Val	missense_variant	3/3	5	NM_032110.3	ENSP00000383909.3
DMRTA2	ENST00000418121.5	c.1550C>T	p.Ala517Val	missense_variant	2/2	1		ENSP00000399370.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1406672 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 697446

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000270

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.00000378

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

Feb 27, 2024

The c.1550C>T (p.A517V) 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 1550, causing the alanine (A) at amino acid position 517 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.65	.;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.051
Sift	Benign	0.078	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.81	P;P
Vest4		0.31
MutPred		0.30		Gain of loop (P = 0.0097);Gain of loop (P = 0.0097);
MVP		0.072
ClinPred		0.37	T
GERP RS		1.8
Varity_R		0.065
gMVP		0.29

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: rs778722829; hg19: chr1-50884416;