15-51481264-AACTTCCATTGCCATC-A

Variant names:

• chr15-51481264-AACTTCCATTGCCATC-A
• rs606231461
• NM_001378457.1:c.5827_5841delGATGGCAATGGAAGT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM4 PP5 BS1_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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D1943D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (1 hom.)
• Consequence: DMXL2 NM_001378457.1 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 1.54
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 81

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• polyendocrine-polyneuropathy syndrome

  Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• hearing loss, autosomal dominant 71

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000259678 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• 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 VariationId is 161414.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378457.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL2	NM_001378457.1	MANE Select	c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 44	NP_001365386.1
	DMXL2	NM_001378458.1		c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 44	NP_001365387.1
	DMXL2	NM_001174116.3		c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 43	NP_001167587.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL2	ENST00000560891.6	TSL:1 MANE Select	c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 44	ENSP00000453267.2
	DMXL2	ENST00000543779.6	TSL:1	c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 43	ENSP00000441858.2
	DMXL2	ENST00000251076.9	TSL:1	c.5827_5841delGATGGCAATGGAAGT	p.Asp1943_Ser1947del	conservative_inframe_deletion	Exon 24 of 43	ENSP00000251076.5

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 101 AN: 152224 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251022 AF XY: 0.000133

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 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.: 1 AF XY: 0.0000729 AC XY: 53 AN XY: 727062

African (AFR) AF: 0.00281 AC: 94 AN: 33476

American (AMR) AF: 0.0000448 AC: 2 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111906

Other (OTH) AF: 0.000166 AC: 10 AN: 60376

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74496

African (AFR) AF: 0.00231 AC: 96 AN: 41574

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000831

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Polyendocrine-polyneuropathy syndrome (2)
-	1	-	not provided (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=17/183	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs606231461; hg19: chr15-51773461;