Variant 15-51449046-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001378457.1(DMXL2):c.9115C>G(p.Leu3039Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DMXL2
NM_001378457.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.65

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:

DMXL2 (HGNC:):

DMXL2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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=0.36114556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMXL2	NM_001378457.1 linkuse as main transcript	c.9115C>G	p.Leu3039Val	missense_variant	44/44	ENST00000560891.6	NP_001365386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMXL2	ENST00000560891.6 linkuse as main transcript	c.9115C>G	p.Leu3039Val	missense_variant	44/44	1	NM_001378457.1	ENSP00000453267.2		H0YLM8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251414

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

The c.9052C>G (p.L3018V) alteration is located in exon 43 (coding exon 43) of the DMXL2 gene. This alteration results from a C to G substitution at nucleotide position 9052, causing the leucine (L) at amino acid position 3018 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

T;.;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.36

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.78

N;N;N

REVEL

Benign

0.18

Sift

Benign

0.12

T;T;T

Sift4G

Benign

0.30

.;.;T

Polyphen

1.0

D;.;.

Vest4

0.50

MutPred

0.44

Loss of catalytic residue at L3017 (P = 0.1234);.;.;

MVP

0.36

MPC

0.79

ClinPred

0.51

GERP RS

4.6

Varity_R

0.14

gMVP

0.62

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