rs141797498

Positions:

• chr9-137834791-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024757.5(EHMT1):​c.3735C>T​(p.Arg1245=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,250 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (4 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.12

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 9-137834791-C-T is Benign according to our data. Variant chr9-137834791-C-T is described in ClinVar as [Benign]. Clinvar id is 96160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137834791-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00183 (279/152268) while in subpopulation AMR AF= 0.00288 (44/15304). AF 95% confidence interval is 0.0022. There are 2 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 279 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.3735C>T	p.Arg1245=	synonymous_variant	27/27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.3735C>T	p.Arg1245=	synonymous_variant	27/27	5	NM_024757.5	ENSP00000417980

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152154 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00142 AC: 354 AN: 248540 Hom.: 2 AF XY: 0.00147 AC XY: 198 AN XY: 134772

Gnomad AFR exome AF: 0.00118

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00235 AC: 3439 AN: 1460982 Hom.: 4 Cov.: 31 AF XY: 0.00226 AC XY: 1646 AN XY: 726850

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00283

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152268 Hom.: 2 Cov.: 34 AF XY: 0.00157 AC XY: 117 AN XY: 74446

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00218 Hom.: 1

Bravo AF: 0.00205

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00243

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	EHMT1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 28, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 18, 2016	- -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 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	-0.33
CADD	Benign	11
DANN	Benign	0.87

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: rs141797498; hg19: chr9-140729243;