chr15-51481264-AACTTCCATTGCCATC-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2PM4PP5BS1_Supporting

The NM_001378457.1(DMXL2):c.5827_5841delGATGGCAATGGAAGT(p.Asp1943_Ser1947del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,956 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 1 hom. )

Consequence

DMXL2
NM_001378457.1 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 1.54

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:

ENSG00000259678 (HGNC:):

ENSG00000259678 links:

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;

PM4

Nonframeshift variant in NON repetitive region in NM_001378457.1.

PP5

Variant 15-51481264-AACTTCCATTGCCATC-A is Pathogenic according to our data. Variant chr15-51481264-AACTTCCATTGCCATC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161414.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00067 (102/152342) while in subpopulation AFR AF= 0.00231 (96/41574). AF 95% confidence interval is 0.00193. There are 0 homozygotes in gnomad4. There are 50 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMXL2	NM_001378457.1 link	c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 44	ENST00000560891.6	NP_001365386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMXL2	ENST00000560891.6 link	c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 44	1	NM_001378457.1	ENSP00000453267.2		H0YLM8

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

101

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251022

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000655

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000773

AC:

113

AN:

1461614

Hom.:

AF XY:

0.0000729

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00281

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000670

AC:

102

AN:

152342

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00231

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.000831

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Polyendocrine-polyneuropathy syndrome

Pathogenic:1Uncertain:1

Sep 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 21, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases

Pathogenic:1

Apr 17, 2020

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3, PS4, PM2, PM3, PM4 -

not provided

Uncertain:1

Aug 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.5827_5841del, results in the deletion of 5 amino acid(s) of the DMXL2 protein (p.Asp1943_Ser1947del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs606231461, gnomAD 0.2%). This variant has been observed in individual(s) with a complex endocrine and neurodevelopmental disorder (PMID: 25248098). ClinVar contains an entry for this variant (Variation ID: 161414). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

Splicing

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