1-155341949-T-C

Position:

• chr1-155341949-T-C

Variant summary

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

The NM_018489.3(ASH1L):​c.8447A>G​(p.Lys2816Arg) variant causes a missense change. 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. K2816Q) 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: 5.88

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.8447A>G	p.Lys2816Arg	missense_variant	25/28	ENST00000392403.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASH1L	ENST00000392403.8	c.8447A>G	p.Lys2816Arg	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

Intellectual disability, autosomal dominant 52 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 23, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.037	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.99	D;D
Vest4		0.29
MutPred		0.25		Loss of methylation at K2821 (P = 0.0047);.;
MVP		0.79
MPC		0.94
ClinPred		0.82	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs1652858406; hg19: chr1-155311740;