9-137716669-A-T

Position:

• chr9-137716669-A-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.129A>T​(p.Ala43Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.009 in 1,598,218 control chromosomes in the GnomAD database, including 829 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (416 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (413 hom.)
• Consequence: EHMT1 NM_024757.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.782

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=-0.75).
• BP6: Variant 9-137716669-A-T is Benign according to our data. Variant chr9-137716669-A-T is described in ClinVar as [Benign]. Clinvar id is 96140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.782 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.129A>T	p.Ala43Ala	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.129A>T	p.Ala43Ala	synonymous_variant	3/27	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6284 AN: 151948 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0274

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.0330

GnomAD3 exomes AF: 0.0122 AC: 2980 AN: 244160 Hom.: 177 AF XY: 0.00932 AC XY: 1232 AN XY: 132202

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.000431

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000235

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00559 AC: 8091 AN: 1446152 Hom.: 413 Cov.: 31 AF XY: 0.00508 AC XY: 3640 AN XY: 717108

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.000237

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000457

Gnomad4 FIN exome AF: 0.0000961

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0414 AC: 6296 AN: 152066 Hom.: 416 Cov.: 32 AF XY: 0.0402 AC XY: 2991 AN XY: 74344

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.0274

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00210

Gnomad4 OTH AF: 0.0327

Alfa AF: 0.0132 Hom.: 32

Bravo AF: 0.0481

Asia WGS AF: 0.00808 AC: 28 AN: 3478

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)	Apr 03, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.0
DANN	Benign	0.85
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

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: rs76684726; hg19: chr9-140611121;