Variant 8-38105725-G-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.175G>A(p.Glu59Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000197 in 1,526,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

ASH2L
NM_004674.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

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:

Genome browser will be placed here

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=0.30455935).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASH2L	NM_004674.5 linkuse as main transcript	c.175G>A	p.Glu59Lys	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.175G>A	p.Glu59Lys	missense_variant	1/16	1	NM_004674.5	Q9UBL3-1
ASH2L	ENST00000517719.5 linkuse as main transcript	c.175G>A	p.Glu59Lys	missense_variant	1/5	3
ASH2L	ENST00000545394.2 linkuse as main transcript	c.-97G>A		5_prime_UTR_variant	1/15	2
ASH2L	ENST00000517496.5 linkuse as main transcript	c.175G>A	p.Glu59Lys	missense_variant, NMD_transcript_variant	1/15	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1374504

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

676448

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:

0.00000187

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

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

Jul 09, 2021

The c.175G>A (p.E59K) 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 175, causing the glutamic acid (E) at amino acid position 59 to be replaced by a lysine (K). 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

0.11

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.097

T;T

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.069

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.31

N;N

REVEL

Benign

0.18

Sift

Uncertain

0.017

D;D

Sift4G

Benign

0.20

T;T

Polyphen

0.96

P;.

Vest4

0.18

MutPred

0.14

Gain of ubiquitination at E59 (P = 0.0094);Gain of ubiquitination at E59 (P = 0.0094);

MVP

0.73

MPC

1.9

ClinPred

0.98

GERP RS

5.8

Varity_R

0.27

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over