rs11137198

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024757.5(EHMT1):c.1162G>A(p.Ala388Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,972 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 20 hom., cov: 33)

Exomes 𝑓: 0.018 ( 321 hom. )

Consequence

EHMT1
NM_024757.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0970

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038109422).

BP6

Variant 9-137744082-G-A is Benign according to our data. Variant chr9-137744082-G-A is described in ClinVar as [Benign]. Clinvar id is 128975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1955/152288) while in subpopulation NFE AF= 0.0183 (1244/68028). AF 95% confidence interval is 0.0174. There are 20 homozygotes in gnomad4. There are 962 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1955 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHMT1	NM_024757.5 linkuse as main transcript	c.1162G>A	p.Ala388Thr	missense_variant	6/27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6 linkuse as main transcript	c.1162G>A	p.Ala388Thr	missense_variant	6/27	5	NM_024757.5	ENSP00000417980		Q9H9B1-1

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1955

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00323

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0110

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0135

AC:

3382

AN:

249848

Hom.:

AF XY:

0.0139

AC XY:

1884

AN XY:

135224

show subpopulations

Gnomad AFR exome

AF:

0.00333

Gnomad AMR exome

AF:

0.00746

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.0224

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0165

GnomAD4 exome

AF:

0.0184

AC:

26939

AN:

1461684

Hom.:

321

Cov.:

AF XY:

0.0185

AC XY:

13454

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.00257

Gnomad4 AMR exome

AF:

0.00754

Gnomad4 ASJ exome

AF:

0.0126

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0126

Gnomad4 FIN exome

AF:

0.0226

Gnomad4 NFE exome

AF:

0.0206

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0128

AC:

1955

AN:

152288

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

962

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00322

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0110

Gnomad4 FIN

AF:

0.0253

Gnomad4 NFE

AF:

0.0183

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0112

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0217

AC:

187

ExAC

AF:

0.0135

AC:

1639

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0176

EpiControl

AF:

0.0166

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Kleefstra syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

2.9

DANN

Benign

0.88

DEOGEN2

Benign

0.048

T;.;T;T;.;T;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.72

T;T;T;T;T;.;T;T

MetaRNN

Benign

0.0038

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.35

N;N;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.20

N;N;.;.;.;.;.;.

REVEL

Benign

0.019

Sift

Benign

0.28

T;T;.;.;.;.;.;.

Sift4G

Benign

0.56

T;T;.;.;.;.;.;.

Polyphen

0.0020

B;B;.;.;.;.;.;.

Vest4

0.0090

MPC

0.045

ClinPred

0.0013

GERP RS

-0.31

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.062

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