rs140506267

Positions:

• chr9-894044-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_021951.3(DMRT1):​c.671A>G​(p.Asn224Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,614,232 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (24 hom.)
• Consequence: DMRT1 NM_021951.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 6.66

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01156497).
• BP6: Variant 9-894044-A-G is Benign according to our data. Variant chr9-894044-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 243009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 224 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMRT1	NM_021951.3	c.671A>G	p.Asn224Ser	missense_variant	3/5	ENST00000382276.8	NP_068770.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMRT1	ENST00000382276.8	c.671A>G	p.Asn224Ser	missense_variant	3/5	1	NM_021951.3	ENSP00000371711	P1
DMRT1	ENST00000569227.1	c.197A>G	p.Asn66Ser	missense_variant	3/5	1		ENSP00000454701
DMRT1	ENST00000564322.1	n.820A>G		non_coding_transcript_exon_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00272 AC: 684 AN: 251454 Hom.: 3 AF XY: 0.00349 AC XY: 474 AN XY: 135900

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0125

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00178 AC: 2596 AN: 1461892 Hom.: 24 Cov.: 32 AF XY: 0.00220 AC XY: 1598 AN XY: 727248

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00474

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0124

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.000967

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00166 AC XY: 124 AN XY: 74498

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0122

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.000963

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00273

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2018	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Sep 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

Non-obstructive azoospermia Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Institute of Reproductive Genetics, University of Münster

Jun 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.98	D;.
Vest4		0.74
MVP		0.59
MPC		0.64
ClinPred		0.046	T
GERP RS		4.8
Varity_R		0.53
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140506267; hg19: chr9-894044;