rs1293246328

Positions:

• chr1-155480700-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2 PP5 BP4 BS2

The NM_018489.3(ASH1L):​c.2170G>T​(p.Ala724Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,374 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASH1L NM_018489.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.04

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ASH1L
• PP5: Variant 1-155480700-C-A is Pathogenic according to our data. Variant chr1-155480700-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 446511.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-155480700-C-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.056046367). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASH1L	NM_018489.3	c.2170G>T	p.Ala724Ser	missense_variant	3/28	ENST00000392403.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASH1L	ENST00000392403.8	c.2170G>T	p.Ala724Ser	missense_variant	3/28	5	NM_018489.3	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 151984 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461374 Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7 AN XY: 726996

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74204

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 52 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 15, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.20	N;N
MutationTaster	Benign	0.98	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.31	N;N
REVEL	Uncertain	0.32
Sift	Benign	0.45	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.0020	B;B
Vest4		0.050
MutPred		0.12		Gain of phosphorylation at A724 (P = 0.0174);Gain of phosphorylation at A724 (P = 0.0174);
MVP		0.32
MPC		0.20
ClinPred		0.41	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.076
gMVP		0.11

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: rs1293246328; hg19: chr1-155450491;