8-38105561-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004674.5(ASH2L):c.11C>A(p.Ala4Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,418,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ASH2L NM_004674.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.348256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASH2L	NM_004674.5	c.11C>A	p.Ala4Glu	missense_variant	1/16	ENST00000343823.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASH2L	ENST00000343823.11	c.11C>A	p.Ala4Glu	missense_variant	1/16	1	NM_004674.5
ASH2L	ENST00000517719.5	c.11C>A	p.Ala4Glu	missense_variant	1/5	3
ASH2L	ENST00000545394.2	c.-261C>A		5_prime_UTR_variant	1/15	2
ASH2L	ENST00000517496.5	c.11C>A	p.Ala4Glu	missense_variant, NMD_transcript_variant	1/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418028 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 702460

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.11C>A (p.A4E) alteration is located in exon 1 (coding exon 1) of the ASH2L gene. This alteration results from a C to A substitution at nucleotide position 11, causing the alanine (A) at amino acid position 4 to be replaced by a glutamic acid (E). 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	0.17
BayesDel_addAF	Benign	0.0053	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.084	T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.28	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.29
MutPred		0.29		Gain of solvent accessibility (P = 0.005);Gain of solvent accessibility (P = 0.005);
MVP		0.51
MPC		0.011
ClinPred		0.84	D
GERP RS		4.3
Varity_R		0.15
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-37963079;