NM_001378457.1:c.3880G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_001378457.1(DMXL2):c.3880G>A(p.Ala1294Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000264 in 1,613,928 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

DMXL2
NM_001378457.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.585

Variant links:

Genes affected

DMXL2 (HGNC:2938): (Dmx like 2) This gene encodes a protein with 12 WD domains. Proteins with WD domains are involved in many functions including participation in signal transduction pathways. Participation of the encoded protein in regulation of the Notch signaling pathway has been demonstrated in vitro using several human cell lines (PMID:20810660). A gene encoding a similar protein is located on chromosome 5. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

DMXL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.004003376).

BP6

Variant 15-51499344-C-T is Benign according to our data. Variant chr15-51499344-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 599427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00158 (240/152298) while in subpopulation AFR AF= 0.00548 (228/41582). AF 95% confidence interval is 0.0049. There are 0 homozygotes in gnomad4. There are 124 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMXL2	NM_001378457.1 link	c.3880G>A	p.Ala1294Thr	missense_variant	Exon 18 of 44	ENST00000560891.6	NP_001365386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DMXL2	ENST00000560891.6 link	c.3880G>A	p.Ala1294Thr	missense_variant	Exon 18 of 44	1	NM_001378457.1	ENSP00000453267.2	H0YLM8
DMXL2	ENST00000543779.6 link	c.3880G>A	p.Ala1294Thr	missense_variant	Exon 18 of 43	1		ENSP00000441858.2	Q8TDJ6-3
DMXL2	ENST00000251076.9 link	c.3880G>A	p.Ala1294Thr	missense_variant	Exon 18 of 43	1		ENSP00000251076.5	Q8TDJ6-1
DMXL2	ENST00000449909.7 link	c.2765-4210G>A		intron_variant	Intron 16 of 40	1		ENSP00000400855.3	Q8TDJ6-2

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

241

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00552

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000588

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000367

AC:

AN:

250756

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.00508

Gnomad AMR exome

AF:

0.000202

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:

0.00000882

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000127

AC:

186

AN:

1461630

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.00430

Gnomad4 AMR exome

AF:

0.000179

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:

0.00000450

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.00158

AC:

240

AN:

152298

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

124

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00548

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.00166

ESP6500AA

AF:

0.00387

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Dec 18, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, and is predicted to be tolerated by multiple functional prediction tools. -

DMXL2-related disorder

Benign:1

May 20, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.013

T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.65

T;T

MetaRNN

Benign

0.0040

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.35

N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

0.080

N;N

REVEL

Benign

0.033

Sift

Benign

0.58

T;T

Polyphen

0.0

B;.

Vest4

0.043

MVP

0.068

MPC

0.20

ClinPred

0.0048

GERP RS

2.7

Varity_R

0.070

gMVP

0.38

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