5-119165286-TAAAAAAAAAAA-TAAAAAAA

Variant names:

• chr5-119165286-TAAAA-T
• rs11301800
• NM_001290321.3:c.4970+21_4970+24delAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000539542.6(DMXL1):​c.4970+7_4970+10delAAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0174 in 867,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 0)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: DMXL1 ENST00000539542.6 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.04
• Publications: 0 publications found

Genes affected

DMXL1 (HGNC:2937): (Dmx like 1) The protein encoded by this gene is a member of the WD repeat superfamily of proteins, which have regulatory functions. This gene is expressed in many tissue types including several types of eye tissue, and it has been associated with ocular phenotypes. In addition, it is upregulated in cultured cells that overexpress growth factor independence 1B, a transcription factor that is essential for hematopoietic cell development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

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

• PM2: Variant has high frequency in the AMR (0.0343) population. However there is too low homozygotes in high coverage region: (expected more than 65, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000539542.6. 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
	DMXL1	NM_001290321.3	MANE Select	c.4970+21_4970+24delAAAA		intron	N/A	NP_001277250.1	F5H269
	DMXL1	NM_001349239.2		c.4970+21_4970+24delAAAA		intron	N/A	NP_001336168.1	F5H269
	DMXL1	NM_001349240.2		c.4970+21_4970+24delAAAA		intron	N/A	NP_001336169.1	Q9Y485

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMXL1	ENST00000539542.6	TSL:1 MANE Select	c.4970+7_4970+10delAAAA		splice_region intron	N/A	ENSP00000439479.1	F5H269
	DMXL1	ENST00000311085.8	TSL:1	c.4970+7_4970+10delAAAA		splice_region intron	N/A	ENSP00000309690.8	Q9Y485
	DMXL1	ENST00000939842.1		c.4325+7_4325+10delAAAA		splice_region intron	N/A	ENSP00000609901.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 9 AN: 114274 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000175

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000359

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0256 AC: 2222 AN: 86686 AF XY: 0.0263

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.0457

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.0365

Gnomad FIN exome AF: 0.00876

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0200 AC: 15087 AN: 752968 Hom.: 0 AF XY: 0.0204 AC XY: 7946 AN XY: 389448

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0217 AC: 378 AN: 17400

American (AMR) AF: 0.0364 AC: 787 AN: 21614

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 353 AN: 16128

East Asian (EAS) AF: 0.0314 AC: 971 AN: 30946

South Asian (SAS) AF: 0.0355 AC: 1657 AN: 46682

European-Finnish (FIN) AF: 0.0162 AC: 598 AN: 36996

Middle Eastern (MID) AF: 0.0205 AC: 53 AN: 2584

European-Non Finnish (NFE) AF: 0.0174 AC: 9530 AN: 546718

Other (OTH) AF: 0.0224 AC: 760 AN: 33900

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000788 AC: 9 AN: 114266 Hom.: 0 Cov.: 0 AF XY: 0.0000732 AC XY: 4 AN XY: 54666

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000328 AC: 1 AN: 30498

American (AMR) AF: 0.000175 AC: 2 AN: 11444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2812

East Asian (EAS) AF: 0.00 AC: 0 AN: 4524

South Asian (SAS) AF: 0.00 AC: 0 AN: 3600

European-Finnish (FIN) AF: 0.000359 AC: 2 AN: 5578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000750 AC: 4 AN: 53324

Other (OTH) AF: 0.00 AC: 0 AN: 1606

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000619235), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 74

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11301800; hg19: chr5-118500981;