Menu
GeneBe

rs754786373

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5

The NM_001378457.1(DMXL2):c.7250G>A(p.Arg2417His) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2417C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

DMXL2
NM_001378457.1 missense

Scores

4
6
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 5.64
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, DMXL2
PP5
Variant 15-51471365-C-T is Pathogenic according to our data. Variant chr15-51471365-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 431430.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DMXL2NM_001378457.1 linkuse as main transcriptc.7250G>A p.Arg2417His missense_variant 29/44 ENST00000560891.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DMXL2ENST00000560891.6 linkuse as main transcriptc.7250G>A p.Arg2417His missense_variant 29/441 NM_001378457.1 A1
ENST00000561007.1 linkuse as main transcriptn.494+4836C>T intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
151952
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251084
Hom.:
0
AF XY:
0.0000516
AC XY:
7
AN XY:
135690
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000793
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461266
Hom.:
0
Cov.:
31
AF XY:
0.0000275
AC XY:
20
AN XY:
726918
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
151952
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74178
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
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:
0.00
Alfa
AF:
0.0000900
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hearing loss, autosomal dominant 71 Pathogenic:2
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 05, 2021- -
Likely pathogenic, criteria provided, single submitterresearchKing Laboratory, University of WashingtonFeb 28, 2023This variant occurred in heterozygosity in a patient with bilateral sensorineural hearing loss of onset <18 years within a single family, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient’s family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is found in 9 heterozygotes on gnomAD. Based on consistently predicted functional effect, literature evidence of pathogenicity, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 31, 2022This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2417 of the DMXL2 protein (p.Arg2417His). This variant is present in population databases (rs754786373, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal dominant non-syndromic hearing loss (PMID: 27657680). ClinVar contains an entry for this variant (Variation ID: 431430). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Benign
-0.068
T
BayesDel_noAF
Benign
-0.14
Cadd
Pathogenic
28
Dann
Pathogenic
1.0
DEOGEN2
Benign
0.21
T;.;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.97
D;D;D
M_CAP
Benign
0.018
T
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.7
L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-2.9
D;D;D
REVEL
Benign
0.20
Sift
Uncertain
0.027
D;D;D
Polyphen
0.99
D;.;.
Vest4
0.65
MutPred
0.26
Loss of MoRF binding (P = 0.0505);.;.;
MVP
0.38
MPC
0.86
ClinPred
0.69
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.31
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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.

Other links and lift over

dbSNP: rs754786373; hg19: chr15-51763562; COSMIC: COSV51848230; COSMIC: COSV51848230; API