8-38105590-G-A

Variant names:

• chr8-38105590-G-A
• rs146282482
• NM_004674.5:c.40G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004674.5(ASH2L):​c.40G>A​(p.Ala14Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,593,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ASH2L NM_004674.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.112
• Publications: 0 publications found

Genes affected

ASH2L (HGNC:744): (ASH2 like, histone lysine methyltransferase complex subunit) Enables beta-catenin binding activity and transcription cis-regulatory region binding activity. Contributes to histone methyltransferase activity (H3-K4 specific). Involved in histone H3-K4 methylation; positive regulation of cell population proliferation; and response to estrogen. Acts upstream of or within cellular response to DNA damage stimulus. Located in nucleus. Part of MLL3/4 complex and Set1C/COMPASS complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000307990 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04794994).
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASH2L	NM_004674.5	c.40G>A	p.Ala14Thr	missense_variant	Exon 1 of 16	ENST00000343823.11	NP_004665.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASH2L	ENST00000343823.11	c.40G>A	p.Ala14Thr	missense_variant	Exon 1 of 16	1	NM_004674.5	ENSP00000340896.5

Frequencies

GnomAD3 genomes AF: 0.000144 AC: 22 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000284 AC: 6 AN: 211080 AF XY: 0.0000173

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1440638 Hom.: 0 Cov.: 31 AF XY: 0.0000112 AC XY: 8 AN XY: 715326

African (AFR) AF: 0.000369 AC: 12 AN: 32532

American (AMR) AF: 0.00 AC: 0 AN: 42720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25692

East Asian (EAS) AF: 0.00 AC: 0 AN: 38314

South Asian (SAS) AF: 0.00 AC: 0 AN: 84224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5278

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1101018

Other (OTH) AF: 0.0000337 AC: 2 AN: 59306

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152370 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74520

African (AFR) AF: 0.000529 AC: 22 AN: 41590

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000928 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.000683 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40G>A (p.A14T) alteration is located in exon 1 (coding exon 1) of the ASH2L gene. This alteration results from a G to A substitution at nucleotide position 40, causing the alanine (A) at amino acid position 14 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		0.11
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.014	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;.
Vest4		0.13
MVP		0.52
MPC		0.011
ClinPred		0.066	T
GERP RS		0.054
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.20
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs146282482; hg19: chr8-37963108;