Genetic Variant DMRTB1:p.Arg96Cys (chr1-53459739-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_033067.3(DMRTB1):c.286C>T(p.Arg96Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,355,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

DMRTB1
NM_033067.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.980

Variant links:

Genes affected

DMRTB1 (HGNC:13913): (DMRT like family B with proline rich C-terminal 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in germ cell development; regulation of transcription by RNA polymerase II; and sex differentiation. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

DMRTB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004362434).

BP6

Variant 1-53459739-C-T is Benign according to our data. Variant chr1-53459739-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2389261.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMRTB1	NM_033067.3 link	c.286C>T	p.Arg96Cys	missense_variant	Exon 1 of 4	ENST00000371445.3	NP_149056.1	Q96MA1I6L9A0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMRTB1	ENST00000371445.3 link	c.286C>T	p.Arg96Cys	missense_variant	Exon 1 of 4	1	NM_033067.3	ENSP00000360500.3		Q96MA1
DMRTB1	ENST00000463126.1 link	n.-237C>T		upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000146

AC:

AN:

151058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000460

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000296

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000623

AC:

AN:

16062

Hom.:

AF XY:

0.000102

AC XY:

AN XY:

9758

show subpopulations

Gnomad AFR exome

AF:

0.00980

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000183

AC:

AN:

1203854

Hom.:

Cov.:

AF XY:

0.0000255

AC XY:

AN XY:

587412

show subpopulations

Gnomad4 AFR exome

AF:

0.000535

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000910

Gnomad4 OTH exome

AF:

0.0000208

GnomAD4 genome

AF:

0.000152

AC:

AN:

151166

Hom.:

Cov.:

AF XY:

0.000203

AC XY:

AN XY:

73886

show subpopulations

Gnomad4 AFR

AF:

0.000483

Gnomad4 AMR

AF:

0.0000658

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000296

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.0000684

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 29, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0021

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.38

REVEL

Benign

0.023

Sift

Benign

0.31

Sift4G

Benign

0.085

Polyphen

0.0070

Vest4

0.044

MutPred

0.20

Loss of methylation at R96 (P = 0.0426);

MVP

0.043

MPC

0.62

ClinPred

0.023

GERP RS

-6.4

Varity_R

0.095

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over