NM_018489.3:c.5087-4071T>C

Variant names:

• chr1-155443139-A-G
• rs11264372
• NM_018489.3:c.5087-4071T>C

Variant summary

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

The NM_018489.3(ASH1L):​c.5087-4071T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,132 control chromosomes in the GnomAD database, including 5,310 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 0.24 (5310 hom., cov: 32)
• Consequence: ASH1L NM_018489.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.714
• Publications: 12 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=-0.9).
• 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.5087-4071T>C		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.5087-4071T>C		intron_variant	Intron 4 of 27	5	NM_018489.3	ENSP00000376204.3

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37117 AN: 152014 Hom.: 5302 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.275

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.244 AC: 37143 AN: 152132 Hom.: 5310 Cov.: 32 AF XY: 0.249 AC XY: 18546 AN XY: 74370

African (AFR) AF: 0.160 AC: 6655 AN: 41502

American (AMR) AF: 0.277 AC: 4229 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 722 AN: 3466

East Asian (EAS) AF: 0.719 AC: 3724 AN: 5176

South Asian (SAS) AF: 0.301 AC: 1455 AN: 4830

European-Finnish (FIN) AF: 0.298 AC: 3149 AN: 10582

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16461 AN: 67982

Other (OTH) AF: 0.249 AC: 525 AN: 2112

Alfa AF: 0.234 Hom.: 1647

Bravo AF: 0.246

Asia WGS AF: 0.492 AC: 1714 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.0
DANN	Benign	0.68
PhyloP100		0.71
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: rs11264372; hg19: chr1-155412930;