1-155338213-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_018489.3(ASH1L):c.8679A>T(p.Lys2893Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: -0.631

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ASH1L
• BP4: Computational evidence support a benign effect (MetaRNN=0.24909925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASH1L	NM_018489.3	c.8679A>T	p.Lys2893Asn	missense_variant	27/28	ENST00000392403.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASH1L	ENST00000392403.8	c.8679A>T	p.Lys2893Asn	missense_variant	27/28	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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	0.0016	D
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.70	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.33	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.014	D;D
Sift4G	Benign	0.098	T;T
Polyphen		0.98	D;D
Vest4		0.40
MutPred		0.21		Loss of ubiquitination at K2898 (P = 9e-04);.;
MVP		0.75
MPC		1.1
ClinPred		0.63	D
GERP RS		0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.072
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: chr1-155308004;