dbSNP rs1057519638: DMRT1:p.Arg111Met (chr9-842170-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_021951.3(DMRT1):c.332G>T(p.Arg111Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DMRT1
NM_021951.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.38

Publications

0 publications found

Variant links:

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]

DMRT1 Gene-Disease associations (from GenCC):

46,XY disorder of sex development
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
46,XX disorder of sex development
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DMRT1 links:

ENSG00000294371 (HGNC:):

ENSG00000294371 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 9-842170-G-T is Pathogenic according to our data. Variant chr9-842170-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 393463.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMRT1	NM_021951.3 link	c.332G>T	p.Arg111Met	missense_variant	Exon 1 of 5	ENST00000382276.8	NP_068770.2	Q9Y5R6-1
DMRT1	XM_006716732.2 link	c.332G>T	p.Arg111Met	missense_variant	Exon 1 of 5		XP_006716795.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DMRT1	ENST00000382276.8 link	c.332G>T	p.Arg111Met	missense_variant	Exon 1 of 5	1	NM_021951.3	ENSP00000371711.3	Q9Y5R6-1
DMRT1	ENST00000564322.1 link	n.481G>T		non_coding_transcript_exon_variant	Exon 1 of 3	1
ENSG00000294371	ENST00000723200.1 link	n.401+4685C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1392034

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687992

African (AFR)

AF:

0.00

AC:

AN:

31810

American (AMR)

AF:

0.00

AC:

AN:

36786

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.00

AC:

AN:

36204

South Asian (SAS)

AF:

0.00

AC:

AN:

79824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082414

Other (OTH)

AF:

0.00

AC:

AN:

58134

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

46,XY sex reversal 4

Pathogenic:1

Feb 27, 2017

Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.80

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

4.0

PhyloP100

9.4

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.82

Loss of MoRF binding (P = 0.0659);

MVP

0.68

MPC

0.79

ClinPred

1.0

GERP RS

4.2

PromoterAI

-0.0061

Neutral

(source)

Varity_R

0.82

gMVP

0.94

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over