rs1553242856

Variant names:

• chr1-155347690-T-TCCTTG
• rs1553242856
• NM_018489.3:c.7764_7768dupCAAGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_018489.3(ASH1L):​c.7764_7768dupCAAGG​(p.Asp2590AlafsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASH1L NM_018489.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.49
• Publications: 1 publications found

Genes affected

ASH1L (HGNC:19088): (ASH1 like histone lysine methyltransferase) This gene encodes a member of the trithorax group of transcriptional activators. The protein contains four AT hooks, a SET domain, a PHD-finger motif, and a bromodomain. It is localized to many small speckles in the nucleus, and also to cell-cell tight junctions. [provided by RefSeq, Jul 2008]

ASH1L Gene-Disease associations (from GenCC):

• syndromic complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 52

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-155347690-T-TCCTTG is Pathogenic according to our data. Variant chr1-155347690-T-TCCTTG is described in ClinVar as Pathogenic. ClinVar VariationId is 446515.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018489.3. 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
	ASH1L	NM_018489.3	MANE Select	c.7764_7768dupCAAGG	p.Asp2590AlafsTer7	frameshift	Exon 20 of 28	NP_060959.2	Q9NR48-2
	ASH1L	NM_001366177.2		c.7779_7783dupCAAGG	p.Asp2595AlafsTer7	frameshift	Exon 20 of 28	NP_001353106.1	Q9NR48-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASH1L	ENST00000392403.8	TSL:5 MANE Select	c.7764_7768dupCAAGG	p.Asp2590AlafsTer7	frameshift	Exon 20 of 28	ENSP00000376204.3	Q9NR48-2
	ASH1L	ENST00000368346.7	TSL:1	c.7779_7783dupCAAGG	p.Asp2595AlafsTer7	frameshift	Exon 20 of 28	ENSP00000357330.3	Q9NR48-1
	ASH1L	ENST00000679133.1		c.7764_7768dupCAAGG	p.Asp2590AlafsTer7	frameshift	Exon 20 of 28	ENSP00000504026.1	A0A7I2V4H9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, autosomal dominant 52 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=10/190	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553242856; hg19: chr1-155317481;