rs1129767

chr9-137743964-G-Achr9-137743964-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024757.5(EHMT1):c.1044G>A(p.Ser348=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 1,613,684 control chromosomes in the GnomAD database, including 28,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S348S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2436 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26387 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.63

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-137743964-G-A is Benign according to our data. Variant chr9-137743964-G-A is described in ClinVar as [Benign]. Clinvar id is 65723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137743964-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.3 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.1044G>A	p.Ser348=	synonymous_variant	6/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.1044G>A	p.Ser348=	synonymous_variant	6/27	5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23203 AN: 152148 Hom.: 2428 Cov.: 32

Gnomad AFR AF: 0.0335

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.203 AC: 50848 AN: 250544 Hom.: 6878 AF XY: 0.198 AC XY: 26846 AN XY: 135514

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.434

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.0963

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.174

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.181 AC: 264306 AN: 1461418 Hom.: 26387 Cov.: 34 AF XY: 0.183 AC XY: 132775 AN XY: 727004

Gnomad4 AFR exome AF: 0.0276

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.181

Gnomad4 NFE exome AF: 0.175

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.153 AC: 23224 AN: 152266 Hom.: 2436 Cov.: 32 AF XY: 0.157 AC XY: 11683 AN XY: 74450

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.308

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.184

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.158

Alfa AF: 0.164 Hom.: 1483

Bravo AF: 0.157

Asia WGS AF: 0.135 AC: 471 AN: 3478

EpiCase AF: 0.179

EpiControl AF: 0.168

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 25, 2014	- -
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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Kleefstra syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.28
Dann	Benign	0.76
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

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

Other links and lift over

dbSNP: rs1129767; hg19: chr9-140638416; COSMIC: COSV58375077; COSMIC: COSV58375077;