Genetic Variant DMRT1:p.Pro71Leu (chr9-842050-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS2

The NM_021951.3(DMRT1):c.212C>T(p.Pro71Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,393,128 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P71R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

DMRT1
NM_021951.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.72

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 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.212C>T	p.Pro71Leu	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.212C>T	p.Pro71Leu	missense	Exon 1 of 5	ENSP00000371711.3	Q9Y5R6-1
DMRT1	ENST00000564322.1	TSL:1	n.361C>T		non_coding_transcript_exon	Exon 1 of 3
ENSG00000294371	ENST00000723200.1		n.401+4805G>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000359

AC:

AN:

1393128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31740

American (AMR)

AF:

0.00

AC:

AN:

36018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35998

South Asian (SAS)

AF:

0.00

AC:

AN:

79722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5066

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1080520

Other (OTH)

AF:

0.00

AC:

AN:

57984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.3

PhyloP100

2.7

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.14

Sift

Uncertain

0.016

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.19

MutPred

0.25

Loss of glycosylation at P71 (P = 0.0092)

MVP

0.33

MPC

0.75

ClinPred

0.99

GERP RS

3.9

PromoterAI

0.013

Neutral

(source)

Varity_R

0.51

gMVP

0.83

Mutation Taster

=73/27

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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