5-119165286-TAAAAAAAAAAA-TAAAAAAAA

Variant names:

• chr5-119165286-TAAA-T
• rs11301800
• NM_001290321.3:c.4970+22_4970+24delAAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The ENST00000539542.6(DMXL1):​c.4970+7_4970+9delAAA variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0551 in 855,778 control chromosomes in the GnomAD database, including 10 homozygotes. 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 0.0051 (8 hom., cov: 0)
  • Exomes 𝑓: 0.063 (2 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00512 (585/114244) while in subpopulation SAS AF = 0.0328 (118/3598). AF 95% confidence interval is 0.028. There are 8 homozygotes in GnomAd4. There are 363 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 gene

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+22_4970+24delAAA		intron	N/A	NP_001277250.1	F5H269
	DMXL1	NM_001349239.2		c.4970+22_4970+24delAAA		intron	N/A	NP_001336168.1	F5H269
	DMXL1	NM_001349240.2		c.4970+22_4970+24delAAA		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+9delAAA		splice_region intron	N/A	ENSP00000439479.1	F5H269
	DMXL1	ENST00000311085.8	TSL:1	c.4970+7_4970+9delAAA		splice_region intron	N/A	ENSP00000309690.8	Q9Y485
	DMXL1	ENST00000939842.1		c.4325+7_4325+9delAAA		splice_region intron	N/A	ENSP00000609901.1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 584 AN: 114254 Hom.: 8 Cov.: 0

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0262

Gnomad ASJ AF: 0.000711

Gnomad EAS AF: 0.0203

Gnomad SAS AF: 0.0326

Gnomad FIN AF: 0.00108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000356

Gnomad OTH AF: 0.00689

GnomAD2 exomes AF: 0.0852 AC: 7389 AN: 86686 AF XY: 0.0874

Gnomad AFR exome AF: 0.0723

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.0899

Gnomad EAS exome AF: 0.129

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.0874

GnomAD4 exome AF: 0.0628 AC: 46593 AN: 741534 Hom.: 2 AF XY: 0.0644 AC XY: 24653 AN XY: 382966

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

African (AFR) AF: 0.0658 AC: 1129 AN: 17146

American (AMR) AF: 0.104 AC: 2211 AN: 21184

Ashkenazi Jewish (ASJ) AF: 0.0684 AC: 1076 AN: 15726

East Asian (EAS) AF: 0.112 AC: 3385 AN: 30268

South Asian (SAS) AF: 0.0958 AC: 4415 AN: 46082

European-Finnish (FIN) AF: 0.0543 AC: 1967 AN: 36222

Middle Eastern (MID) AF: 0.0648 AC: 165 AN: 2546

European-Non Finnish (NFE) AF: 0.0557 AC: 30009 AN: 539090

Other (OTH) AF: 0.0672 AC: 2236 AN: 33270

⚠️ 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: 0.00512 AC: 585 AN: 114244 Hom.: 8 Cov.: 0 AF XY: 0.00664 AC XY: 363 AN XY: 54656

African (AFR) AF: 0.00121 AC: 37 AN: 30498

American (AMR) AF: 0.0261 AC: 299 AN: 11442

Ashkenazi Jewish (ASJ) AF: 0.000711 AC: 2 AN: 2814

East Asian (EAS) AF: 0.0203 AC: 92 AN: 4524

South Asian (SAS) AF: 0.0328 AC: 118 AN: 3598

European-Finnish (FIN) AF: 0.00108 AC: 6 AN: 5578

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

European-Non Finnish (NFE) AF: 0.000356 AC: 19 AN: 53306

Other (OTH) AF: 0.00748 AC: 12 AN: 1604

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)		0.030		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;