9-841971-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021951.3(DMRT1):c.133T>A(p.Ser45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,583,340 control chromosomes in the GnomAD database, including 22,373 homozygotes. 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2066 hom., cov: 32)
  • Exomes 𝑓: 0.15 (20307 hom.)
• Consequence: DMRT1 NM_021951.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.90

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3878942E-4).
• BP6: Variant 9-841971-T-A is Benign according to our data. Variant chr9-841971-T-A is described in ClinVar as [Benign]. Clinvar id is 1280947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMRT1	NM_021951.3	c.133T>A	p.Ser45Thr	missense_variant	1/5	ENST00000382276.8
DMRT1	XM_006716732.2	c.133T>A	p.Ser45Thr	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMRT1	ENST00000382276.8	c.133T>A	p.Ser45Thr	missense_variant	1/5	1	NM_021951.3	P1
DMRT1	ENST00000564322.1	n.282T>A		non_coding_transcript_exon_variant	1/3	1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22338 AN: 152036 Hom.: 2057 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.191 AC: 36172 AN: 189484 Hom.: 4260 AF XY: 0.191 AC XY: 19970 AN XY: 104430

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.207

Gnomad EAS exome AF: 0.480

Gnomad SAS exome AF: 0.254

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.154 AC: 220532 AN: 1431186 Hom.: 20307 Cov.: 34 AF XY: 0.157 AC XY: 111160 AN XY: 709092

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.194

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.477

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.147 AC: 22362 AN: 152154 Hom.: 2066 Cov.: 32 AF XY: 0.150 AC XY: 11124 AN XY: 74396

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.172

Alfa AF: 0.143 Hom.: 544

Bravo AF: 0.150

TwinsUK AF: 0.137 AC: 508

ALSPAC AF: 0.135 AC: 519

ESP6500AA AF: 0.0987 AC: 381

ESP6500EA AF: 0.123 AC: 945

ExAC AF: 0.163 AC: 18462

Asia WGS AF: 0.367 AC: 1276 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
Cadd	Benign	5.3
Dann	Benign	0.79
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.00014	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.013
Sift	Benign	0.47	T
Sift4G	Benign	0.49	T
Polyphen		0.016	B
Vest4		0.028
MPC		0.18
ClinPred		0.0027	T
GERP RS		-1.9
Varity_R		0.045
gMVP		0.35

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: rs3739583; hg19: chr9-841971; COSMIC: COSV66519748; COSMIC: COSV66519748;