Genetic Variant DMRT1:p.Gly59Arg (chr9-842013-G-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021951.3(DMRT1):c.175G>C(p.Gly59Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000857 in 1,400,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

DMRT1
NM_021951.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.03

Publications

2 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_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.119877696).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMRT1	NM_021951.3	MANE Select	c.175G>C	p.Gly59Arg	missense	Exon 1 of 5	NP_068770.2	Q9Y5R6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMRT1	ENST00000382276.8	TSL:1 MANE Select	c.175G>C	p.Gly59Arg	missense	Exon 1 of 5	ENSP00000371711.3	Q9Y5R6-1
DMRT1	ENST00000564322.1	TSL:1	n.324G>C		non_coding_transcript_exon	Exon 1 of 3
ENSG00000294371	ENST00000723200.1		n.401+4842C>G		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

146132

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000857

AC:

AN:

1400130

Hom.:

Cov.:

AF XY:

0.00000868

AC XY:

AN XY:

691568

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31936

American (AMR)

AF:

0.0000275

AC:

AN:

36412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25204

East Asian (EAS)

AF:

0.00

AC:

AN:

36472

South Asian (SAS)

AF:

0.00

AC:

AN:

80320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4768

European-Non Finnish (NFE)

AF:

0.00000923

AC:

AN:

1082926

Other (OTH)

AF:

0.00

AC:

AN:

58078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000944

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.52

M_CAP

Benign

0.0057

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

2.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.68

REVEL

Benign

0.033

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.038

Polyphen

0.0070

Vest4

0.18

MutPred

0.25

Gain of MoRF binding (P = 0.0046)

MVP

0.15

MPC

0.62

ClinPred

0.65

GERP RS

3.1

PromoterAI

0.0021

Neutral

(source)

Varity_R

0.15

gMVP

0.40

Mutation Taster

=86/14

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over