1-155442246-C-T

Variant names:

• chr1-155442246-C-T
• rs11264371
• NM_018489.3:c.5087-3178G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018489.3(ASH1L):​c.5087-3178G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 151,712 control chromosomes in the GnomAD database, including 7,488 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7488 hom., cov: 29)
• Consequence: ASH1L NM_018489.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.238
• Publications: 16 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: G2P, Labcorp Genetics (formerly Invitae), Illumina
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASH1L	NM_018489.3	c.5087-3178G>A		intron_variant	Intron 4 of 27	ENST00000392403.8	NP_060959.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASH1L	ENST00000392403.8	c.5087-3178G>A		intron_variant	Intron 4 of 27	5	NM_018489.3	ENSP00000376204.3

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45606 AN: 151594 Hom.: 7470 Cov.: 29

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.288

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.301 AC: 45665 AN: 151712 Hom.: 7488 Cov.: 29 AF XY: 0.304 AC XY: 22535 AN XY: 74136

African (AFR) AF: 0.361 AC: 14946 AN: 41374

American (AMR) AF: 0.293 AC: 4454 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3464

East Asian (EAS) AF: 0.720 AC: 3700 AN: 5142

South Asian (SAS) AF: 0.301 AC: 1439 AN: 4786

European-Finnish (FIN) AF: 0.298 AC: 3126 AN: 10488

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16459 AN: 67922

Other (OTH) AF: 0.284 AC: 597 AN: 2104

Alfa AF: 0.263 Hom.: 21918

Bravo AF: 0.311

Asia WGS AF: 0.507 AC: 1766 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.28
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11264371; hg19: chr1-155412037;