1-155341950-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_018489.3(ASH1L):c.8446A>C(p.Lys2816Gln) variant causes a missense 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2816R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASH1L NM_018489.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ASH1L

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASH1L	NM_018489.3	c.8446A>C	p.Lys2816Gln	missense_variant	25/28	ENST00000392403.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASH1L	ENST00000392403.8	c.8446A>C	p.Lys2816Gln	missense_variant	25/28	5	NM_018489.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2024

The c.8446A>C (p.K2816Q) alteration is located in exon 25 (coding exon 24) of the ASH1L gene. This alteration results from a A to C substitution at nucleotide position 8446, causing the lysine (K) at amino acid position 2816 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.079	T;T
Polyphen		1.0	D;D
Vest4		0.45
MutPred		0.28		Loss of methylation at K2821 (P = 0.0033);.;
MVP		0.79
MPC		1.8
ClinPred		0.89	D
GERP RS		5.3
Varity_R		0.26
gMVP		0.43

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155311741;