rs11137244

chr9-137813437-G-Achr9-137813437-G-Cchr9-137813437-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.3087G>A(p.Val1029=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,613,706 control chromosomes in the GnomAD database, including 963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (486 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (477 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.11

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=-0.61).
• BP6: Variant 9-137813437-G-A is Benign according to our data. Variant chr9-137813437-G-A is described in ClinVar as [Benign]. Clinvar id is 128979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137813437-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.3087G>A	p.Val1029=	synonymous_variant	21/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.3087G>A	p.Val1029=	synonymous_variant	21/27	5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6793 AN: 152134 Hom.: 486 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0128 AC: 3212 AN: 250336 Hom.: 193 AF XY: 0.00981 AC XY: 1328 AN XY: 135418

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.00215

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00591 AC: 8637 AN: 1461454 Hom.: 477 Cov.: 33 AF XY: 0.00535 AC XY: 3886 AN XY: 727016

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0136

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.0000940

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0447 AC: 6801 AN: 152252 Hom.: 486 Cov.: 33 AF XY: 0.0434 AC XY: 3234 AN XY: 74440

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.0266

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.0340

Alfa AF: 0.0142 Hom.: 148

Bravo AF: 0.0513

Asia WGS AF: 0.0110 AC: 38 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00255

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 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. -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	5.8
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11137244; hg19: chr9-140707889;