rs11137198

Positions:

• chr9-137744082-G-A
• chr9-137744082-G-C
• chr9-137744082-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024757.5(EHMT1):​c.1162G>A​(p.Ala388Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,613,972 control chromosomes in the GnomAD database, including 341 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 33)
  • Exomes 𝑓: 0.018 (321 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0970

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038109422).
• BP6: Variant 9-137744082-G-A is Benign according to our data. Variant chr9-137744082-G-A is described in ClinVar as [Benign]. Clinvar id is 128975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0128 (1955/152288) while in subpopulation NFE AF= 0.0183 (1244/68028). AF 95% confidence interval is 0.0174. There are 20 homozygotes in gnomad4. There are 962 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1955 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.1162G>A	p.Ala388Thr	missense_variant	6/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.1162G>A	p.Ala388Thr	missense_variant	6/27	5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1955 AN: 152170 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.0135 AC: 3382 AN: 249848 Hom.: 38 AF XY: 0.0139 AC XY: 1884 AN XY: 135224

Gnomad AFR exome AF: 0.00333

Gnomad AMR exome AF: 0.00746

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.0224

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0184 AC: 26939 AN: 1461684 Hom.: 321 Cov.: 34 AF XY: 0.0185 AC XY: 13454 AN XY: 727150

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.00754

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.0226

Gnomad4 NFE exome AF: 0.0206

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0128 AC: 1955 AN: 152288 Hom.: 20 Cov.: 33 AF XY: 0.0129 AC XY: 962 AN XY: 74478

Gnomad4 AFR AF: 0.00322

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.0253

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.0154 Hom.: 49

Bravo AF: 0.0112

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0217 AC: 187

ExAC AF: 0.0135 AC: 1639

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0166

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. -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.9
DANN	Benign	0.88
DEOGEN2	Benign	0.048	T;.;T;T;.;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.72	T;T;T;T;T;.;T;T
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.20	N;N;.;.;.;.;.;.
REVEL	Benign	0.019
Sift	Benign	0.28	T;T;.;.;.;.;.;.
Sift4G	Benign	0.56	T;T;.;.;.;.;.;.
Polyphen		0.0020	B;B;.;.;.;.;.;.
Vest4		0.0090
MPC		0.045
ClinPred		0.0013	T
GERP RS		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.056
gMVP		0.062

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: rs11137198; hg19: chr9-140638534;