rs12724079

Variant names:

• chr1-155464151-T-C
• rs12724079
• NM_018489.3:c.4985-4253A>G

Variant summary

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

The NM_018489.3(ASH1L):​c.4985-4253A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 151,938 control chromosomes in the GnomAD database, including 24,645 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 0.54 (24645 hom., cov: 31)
• Consequence: ASH1L NM_018489.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.293
• 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=-0.65).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASH1L	NM_018489.3	c.4985-4253A>G		intron_variant	Intron 3 of 27	ENST00000392403.8	NP_060959.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASH1L	ENST00000392403.8	c.4985-4253A>G		intron_variant	Intron 3 of 27	5	NM_018489.3	ENSP00000376204.3

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81505 AN: 151820 Hom.: 24642 Cov.: 31

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.736

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.615

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.694

Gnomad NFE AF: 0.683

Gnomad OTH AF: 0.579

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

GnomAD4 genome AF: 0.537 AC: 81518 AN: 151938 Hom.: 24645 Cov.: 31 AF XY: 0.536 AC XY: 39818 AN XY: 74242

African (AFR) AF: 0.248 AC: 10263 AN: 41446

American (AMR) AF: 0.614 AC: 9368 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.736 AC: 2553 AN: 3468

East Asian (EAS) AF: 0.278 AC: 1437 AN: 5166

South Asian (SAS) AF: 0.617 AC: 2970 AN: 4816

European-Finnish (FIN) AF: 0.622 AC: 6542 AN: 10524

Middle Eastern (MID) AF: 0.685 AC: 200 AN: 292

European-Non Finnish (NFE) AF: 0.683 AC: 46392 AN: 67954

Other (OTH) AF: 0.584 AC: 1235 AN: 2114

Alfa AF: 0.636 Hom.: 20259

Bravo AF: 0.518

Asia WGS AF: 0.430 AC: 1494 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.90
PhyloP100		0.29
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: rs12724079; hg19: chr1-155433942;