9-841914-G-A

Variant summary

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

The NM_021951.3(DMRT1):c.76G>A(p.Gly26Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,930 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DMRT1 NM_021951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.898

Genes affected

DMRT1 (HGNC:2934): (doublesex and mab-3 related transcription factor 1) This gene is found in a cluster with two other members of the gene family, having in common a zinc finger-like DNA-binding motif (DM domain). The DM domain is an ancient, conserved component of the vertebrate sex-determining pathway that is also a key regulator of male development in flies and nematodes. This gene exhibits a gonad-specific and sexually dimorphic expression pattern. Defective testicular development and XY feminization occur when this gene is hemizygous. [provided by RefSeq, Jul 2008]

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=0.14297473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMRT1	NM_021951.3	c.76G>A	p.Gly26Ser	missense_variant	1/5	ENST00000382276.8
DMRT1	XM_006716732.2	c.76G>A	p.Gly26Ser	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMRT1	ENST00000382276.8	c.76G>A	p.Gly26Ser	missense_variant	1/5	1	NM_021951.3	P1
DMRT1	ENST00000564322.1	n.225G>A		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1456930 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 724290

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

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 03, 2022

The c.76G>A (p.G26S) alteration is located in exon 1 (coding exon 1) of the DMRT1 gene. This alteration results from a G to A substitution at nucleotide position 76, causing the glycine (G) at amino acid position 26 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	Benign	0.096
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.078	T
Eigen	Benign	0.037
Eigen_PC	Benign	0.041
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	0.84	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.055
Sift	Benign	0.030	D
Sift4G	Benign	0.24	T
Polyphen		0.82	P
Vest4		0.10
MutPred		0.17		Gain of glycosylation at G26 (P = 0.0041);
MVP		0.28
MPC		0.74
ClinPred		0.69	D
GERP RS		3.9
Varity_R		0.15
gMVP		0.56

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: rs773825242; hg19: chr9-841914;