Variant 8-38105561-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.70

Variant links:

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]

ASH2L links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.11C>A	p.Ala4Glu	missense_variant	1/16	ENST00000343823.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
ASH2L	ENST00000343823.11 linkuse as main transcript	c.11C>A	p.Ala4Glu	missense_variant	1/16	1	NM_004674.5	Q9UBL3-1
ASH2L	ENST00000517719.5 linkuse as main transcript	c.11C>A	p.Ala4Glu	missense_variant	1/5	3
ASH2L	ENST00000545394.2 linkuse as main transcript	c.-261C>A		5_prime_UTR_variant	1/15	2
ASH2L	ENST00000517496.5 linkuse as main transcript	c.11C>A	p.Ala4Glu	missense_variant, NMD_transcript_variant	1/15	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1418028

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702460

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.084

T;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.75

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

1.0

D;D;N

PrimateAI

Uncertain

0.75

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over