rs35943616

Positions:

• chr9-137813138-C-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.3000C>T​(p.Pro1000=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,611,890 control chromosomes in the GnomAD database, including 4,507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (2380 hom., cov: 33)
  • Exomes 𝑓: 0.010 (2127 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.12

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=-0.77).
• BP6: Variant 9-137813138-C-T is Benign according to our data. Variant chr9-137813138-C-T is described in ClinVar as [Benign]. Clinvar id is 96151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.3000C>T	p.Pro1000=	synonymous_variant	20/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.3000C>T	p.Pro1000=	synonymous_variant	20/27	5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.0970 AC: 14756 AN: 152078 Hom.: 2368 Cov.: 33

Gnomad AFR AF: 0.336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.0789

GnomAD3 exomes AF: 0.0258 AC: 6434 AN: 249276 Hom.: 971 AF XY: 0.0187 AC XY: 2532 AN XY: 135072

Gnomad AFR exome AF: 0.343

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00315

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000978

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0101 AC: 14785 AN: 1459694 Hom.: 2127 Cov.: 32 AF XY: 0.00859 AC XY: 6241 AN XY: 726298

Gnomad4 AFR exome AF: 0.347

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00433

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000579

Gnomad4 OTH exome AF: 0.0219

GnomAD4 genome AF: 0.0973 AC: 14810 AN: 152196 Hom.: 2380 Cov.: 33 AF XY: 0.0929 AC XY: 6913 AN XY: 74422

Gnomad4 AFR AF: 0.337

Gnomad4 AMR AF: 0.0376

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00348

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.0781

Alfa AF: 0.0427 Hom.: 475

Bravo AF: 0.112

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00136

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	Eurofins Ntd Llc (ga)	May 21, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Mar 16, 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
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.16
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs35943616; hg19: chr9-140707590;