9-137619042-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024757.5(EHMT1):c.14A>G(p.Asp5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000837 in 955,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000069 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.239

Variant links:

Genes affected

EHMT1 (HGNC:24650): (euchromatic histone lysine methyltransferase 1) The protein encoded by this gene is a histone methyltransferase that methylates the lysine-9 position of histone H3. This action marks the genomic region packaged with these methylated histones for transcriptional repression. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome, also known as Kleefstra syndrome). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2017]

EHMT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18180445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5 linkuse as main transcript	c.14A>G	p.Asp5Gly	missense_variant	1/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6 linkuse as main transcript	c.14A>G	p.Asp5Gly	missense_variant	1/27	5	NM_024757.5		Q9H9B1-1

Frequencies

GnomAD3 genomes

AF:

0.00000690

AC:

AN:

144830

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:

0.0000153

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000863

AC:

AN:

811054

Hom.:

Cov.:

AF XY:

0.0000133

AC XY:

AN XY:

375046

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:

0.00000945

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000690

AC:

AN:

144830

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70424

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:

0.0000153

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Kleefstra syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 5 of the EHMT1 protein (p.Asp5Gly). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with EHMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2043325). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.091

T;.;T

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.50

T;T;T

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.051

Sift

Benign

0.099

T;T;.

Sift4G

Benign

0.11

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.11

MutPred

0.21

Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);

MVP

0.52

MPC

0.055

ClinPred

0.048

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.094

gMVP

0.10

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

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