chr9-137716894-T-G

Position:

• chr9-137716894-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024757.5(EHMT1):​c.354T>G​(p.Ser118=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000359 in 1,613,196 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.28

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=-0.87).
• BP6: Variant 9-137716894-T-G is Benign according to our data. Variant chr9-137716894-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 96158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137716894-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00154 (234/152250) while in subpopulation AFR AF= 0.00501 (208/41530). AF 95% confidence interval is 0.00445. There are 1 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 234 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.354T>G	p.Ser118=	synonymous_variant	3/27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.354T>G	p.Ser118=	synonymous_variant	3/27	5	NM_024757.5	ENSP00000417980

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152132 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000462 AC: 116 AN: 250944 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135786

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000236 AC: 345 AN: 1460946 Hom.: 2 Cov.: 31 AF XY: 0.000235 AC XY: 171 AN XY: 726748

Gnomad4 AFR exome AF: 0.00648

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.000696

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152250 Hom.: 1 Cov.: 31 AF XY: 0.00156 AC XY: 116 AN XY: 74418

Gnomad4 AFR AF: 0.00501

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000901 Hom.: 0

Bravo AF: 0.00180

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	EHMT1: BP4, BP7, BS1 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 08, 2013

- -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2016

This alteration is classified as likely 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	-0.87
CADD	Benign	0.10
DANN	Benign	0.38

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: rs142271310; hg19: chr9-140611346;