rs1553241570

Variant names:

• chr1-155342040-C-G
• rs1553241570
• NM_018489.3:c.8356G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_018489.3(ASH1L):​c.8356G>C​(p.Ala2786Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASH1L NM_018489.3 missense
• 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), Illumina, G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889
• PP5: Variant 1-155342040-C-G is Pathogenic according to our data. Variant chr1-155342040-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 446517.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.8356G>C	p.Ala2786Pro	missense	Exon 25 of 28	NP_060959.2	Q9NR48-2
	ASH1L	NM_001366177.2		c.8371G>C	p.Ala2791Pro	missense	Exon 25 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.8356G>C	p.Ala2786Pro	missense	Exon 25 of 28	ENSP00000376204.3	Q9NR48-2
	ASH1L	ENST00000368346.7	TSL:1	c.8371G>C	p.Ala2791Pro	missense	Exon 25 of 28	ENSP00000357330.3	Q9NR48-1
	ASH1L	ENST00000679133.1		c.8356G>C	p.Ala2786Pro	missense	Exon 25 of 28	ENSP00000504026.1	A0A7I2V4H9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.2	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.66		Gain of methylation at K2796 (P = 0.0504)
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.86
Mutation Taster		=18/82	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1553241570; hg19: chr1-155311831;