rs202097707

chr9-137757912-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024757.5(EHMT1):c.1402G>A(p.Ala468Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,613,962 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.378

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01828733).
• BP6: Variant 9-137757912-G-A is Benign according to our data. Variant chr9-137757912-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 366009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137757912-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.1402G>A	p.Ala468Thr	missense_variant	9/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.1402G>A	p.Ala468Thr	missense_variant	9/27	5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 27 AN: 251462 Hom.: 0 AF XY: 0.000125 AC XY: 17 AN XY: 135908

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1461838 Hom.: 1 Cov.: 31 AF XY: 0.000146 AC XY: 106 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000178

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.0000680

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	EHMT1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2020	- -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2021

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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	1.2
Dann	Benign	0.65
DEOGEN2	Benign	0.050	T;.;T;T;.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.53	T;T;T;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.018	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N;N;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.23	N;N;.;.;.;.;.
REVEL	Benign	0.030
Sift	Benign	0.68	T;T;.;.;.;.;.
Sift4G	Benign	0.58	T;T;.;.;.;.;T
Polyphen		0.0010	B;B;.;.;.;.;.
Vest4		0.039
MVP		0.25
MPC		0.045
ClinPred		0.0039	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.021
gMVP		0.039

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: rs202097707; hg19: chr9-140652364;