rs146125583

Positions:

• chr9-137754300-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024757.5(EHMT1):​c.1369+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00968 in 1,613,704 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0078 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (108 hom.)
• Consequence: EHMT1 NM_024757.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.187

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-137754300-C-T is Benign according to our data. Variant chr9-137754300-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96141.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00775 (1180/152176) while in subpopulation NFE AF= 0.0124 (843/67986). AF 95% confidence interval is 0.0117. There are 6 homozygotes in gnomad4. There are 518 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1180 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.1369+9C>T		intron_variant		ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.1369+9C>T		intron_variant		5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.00776 AC: 1180 AN: 152058 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00675 AC: 1695 AN: 251064 Hom.: 14 AF XY: 0.00685 AC XY: 929 AN XY: 135704

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00601

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00189

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.00988 AC: 14447 AN: 1461528 Hom.: 108 Cov.: 32 AF XY: 0.00979 AC XY: 7116 AN XY: 727046

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00624

Gnomad4 ASJ exome AF: 0.00425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.00238

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.00830

GnomAD4 genome AF: 0.00775 AC: 1180 AN: 152176 Hom.: 6 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74414

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.0102 Hom.: 1

Bravo AF: 0.00840

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 15, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2014	- -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

EHMT1: BS1, BS2 -

EHMT1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.67
DANN	Benign	0.55

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: rs146125583; hg19: chr9-140648752;