15-51499362-A-G

Position:

chr15-51499362-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001378457.1(DMXL2):c.3862T>C(p.Ser1288Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,613,468 control chromosomes in the GnomAD database, including 206,286 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 Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18567 hom., cov: 32)

Exomes 𝑓: 0.51 ( 187719 hom. )

Consequence

DMXL2
NM_001378457.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.269

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DMXL2. . Gene score misZ 2.3662 (greater than the threshold 3.09). Trascript score misZ 3.2988 (greater than threshold 3.09). GenCC has associacion of gene with polyendocrine-polyneuropathy syndrome, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss, hearing loss, autosomal dominant 71, developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 81.

BP4

Computational evidence support a benign effect (MetaRNN=0.0010027885).

BP6

Variant 15-51499362-A-G is Benign according to our data. Variant chr15-51499362-A-G is described in ClinVar as [Benign]. Clinvar id is 1255511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMXL2	NM_001378457.1 linkuse as main transcript	c.3862T>C	p.Ser1288Pro	missense_variant	18/44	ENST00000560891.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMXL2	ENST00000560891.6 linkuse as main transcript	c.3862T>C	p.Ser1288Pro	missense_variant	18/44	1	NM_001378457.1	A1
DMXL2	ENST00000543779.6 linkuse as main transcript	c.3862T>C	p.Ser1288Pro	missense_variant	18/43	1		P4	Q8TDJ6-3
DMXL2	ENST00000251076.9 linkuse as main transcript	c.3862T>C	p.Ser1288Pro	missense_variant	18/43	1		A1	Q8TDJ6-1
DMXL2	ENST00000449909.7 linkuse as main transcript	c.2765-4228T>C		intron_variant		1			Q8TDJ6-2

Frequencies

GnomAD3 genomes

AF:

0.490

AC:

74459

AN:

151852

Hom.:

18548

Cov.:

show subpopulations

Gnomad AFR

AF:

0.444

Gnomad AMI

AF:

0.705

Gnomad AMR

AF:

0.501

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.432

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.542

Gnomad MID

AF:

0.462

Gnomad NFE

AF:

0.520

Gnomad OTH

AF:

0.477

GnomAD3 exomes

AF:

0.492

AC:

123222

AN:

250686

Hom.:

30852

AF XY:

0.488

AC XY:

66164

AN XY:

135588

show subpopulations

Gnomad AFR exome

AF:

0.442

Gnomad AMR exome

AF:

0.519

Gnomad ASJ exome

AF:

0.389

Gnomad EAS exome

AF:

0.416

Gnomad SAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.548

Gnomad NFE exome

AF:

0.520

Gnomad OTH exome

AF:

0.474

GnomAD4 exome

AF:

0.506

AC:

739086

AN:

1461498

Hom.:

187719

Cov.:

AF XY:

0.503

AC XY:

366016

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.449

Gnomad4 AMR exome

AF:

0.518

Gnomad4 ASJ exome

AF:

0.390

Gnomad4 EAS exome

AF:

0.443

Gnomad4 SAS exome

AF:

0.431

Gnomad4 FIN exome

AF:

0.552

Gnomad4 NFE exome

AF:

0.517

Gnomad4 OTH exome

AF:

0.487

GnomAD4 genome

AF:

0.490

AC:

74527

AN:

151970

Hom.:

18567

Cov.:

AF XY:

0.489

AC XY:

36348

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.444

Gnomad4 AMR

AF:

0.501

Gnomad4 ASJ

AF:

0.386

Gnomad4 EAS

AF:

0.433

Gnomad4 SAS

AF:

0.425

Gnomad4 FIN

AF:

0.542

Gnomad4 NFE

AF:

0.520

Gnomad4 OTH

AF:

0.481

Alfa

AF:

0.498

Hom.:

45115

Bravo

AF:

0.488

TwinsUK

AF:

0.507

AC:

1879

ALSPAC

AF:

0.521

AC:

2009

ESP6500AA

AF:

0.433

AC:

1902

ESP6500EA

AF:

0.505

AC:

4332

ExAC

AF:

0.492

AC:

59752

Asia WGS

AF:

0.418

AC:

1452

AN:

3478

EpiCase

AF:

0.504

EpiControl

AF:

0.495

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 81

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Polyendocrine-polyneuropathy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hearing loss, autosomal dominant 71

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.015

T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.080

T;T

MetaRNN

Benign

0.0010

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.40

N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.020

N;N

REVEL

Benign

0.027

Sift

Benign

0.23

T;T

Polyphen

0.0

B;.

Vest4

0.030

MPC

0.26

ClinPred

0.0071

GERP RS

1.7

Varity_R

0.085

gMVP

0.21

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