9-846952-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_021951.3(DMRT1):c.355-8G>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,614,048 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (34 hom.)
• Consequence: DMRT1 NM_021951.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001418
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.13

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-846952-G-C is Benign according to our data. Variant chr9-846952-G-C is described in ClinVar as [Benign]. Clinvar id is 768275.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.013 (1977/152314) while in subpopulation AFR AF= 0.0428 (1779/41562). AF 95% confidence interval is 0.0411. There are 45 homozygotes in gnomad4. There are 916 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1960 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMRT1	NM_021951.3	c.355-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000382276.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMRT1	ENST00000382276.8	c.355-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021951.3	P1
DMRT1	ENST00000569227.1	c.-120-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
DMRT1	ENST00000564322.1	n.504-8G>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1960 AN: 152196 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00399 AC: 997 AN: 249900 Hom.: 21 AF XY: 0.00320 AC XY: 432 AN XY: 135182

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.00442

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000712

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00176 AC: 2571 AN: 1461734 Hom.: 34 Cov.: 31 AF XY: 0.00160 AC XY: 1162 AN XY: 727164

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00295

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000564

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.0130 AC: 1977 AN: 152314 Hom.: 45 Cov.: 32 AF XY: 0.0123 AC XY: 916 AN XY: 74472

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.00289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00438 Hom.: 2

Bravo AF: 0.0146

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	11
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
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: rs55905583; hg19: chr9-846952;