9-846956-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_021951.3(DMRT1):c.355-4C>T 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 0.000427 in 1,613,996 control chromosomes in the GnomAD database, including 2 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 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (2 hom.)
• Consequence: DMRT1 NM_021951.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001498
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.734

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 9-846956-C-T is Benign according to our data. Variant chr9-846956-C-T is described in ClinVar as [Benign]. Clinvar id is 2056951.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMRT1	NM_021951.3	c.355-4C>T		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.355-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_021951.3	P1
DMRT1	ENST00000569227.1	c.-120-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
DMRT1	ENST00000564322.1	n.504-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000572 AC: 143 AN: 249976 Hom.: 0 AF XY: 0.000533 AC XY: 72 AN XY: 135210

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00467

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000427 AC: 624 AN: 1461788 Hom.: 2 Cov.: 31 AF XY: 0.000441 AC XY: 321 AN XY: 727192

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.000416

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000797 Hom.: 0

Bravo AF: 0.000355

EpiCase AF: 0.000709

EpiControl AF: 0.000652

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 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	5.8
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.0
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: rs200261277; hg19: chr9-846956;