rs78104547

chr9-137716688-G-A

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.148G>A(p.Ala50Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,606,096 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A50V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (42 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.475

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=0.0017711818).
• BP6: Variant 9-137716688-G-A is Benign according to our data. Variant chr9-137716688-G-A is described in ClinVar as [Benign]. Clinvar id is 128976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137716688-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00209 (318/152176) while in subpopulation EAS AF= 0.0515 (267/5188). AF 95% confidence interval is 0.0464. There are 8 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 319 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.148G>A	p.Ala50Thr	missense_variant	3/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.148G>A	p.Ala50Thr	missense_variant	3/27	5	NM_024757.5

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152058 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0515

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00436 AC: 1084 AN: 248620 Hom.: 29 AF XY: 0.00375 AC XY: 505 AN XY: 134584

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0550

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00142 AC: 2059 AN: 1453920 Hom.: 42 Cov.: 31 AF XY: 0.00137 AC XY: 992 AN XY: 721902

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0399

Gnomad4 SAS exome AF: 0.00151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000913

Gnomad4 OTH exome AF: 0.00395

GnomAD4 genome AF: 0.00209 AC: 318 AN: 152176 Hom.: 8 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74384

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0515

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00187 Hom.: 8

Bravo AF: 0.00249

ExAC AF: 0.00420 AC: 510

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

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)	Feb 14, 2014	- -

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 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 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	5.8
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;T;T;T;T;T;.;.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.83	N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.050
Sift	Benign	0.076	T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.25	T;T;T;D;.;.;T;T;.;T
Polyphen		0.031	B;B;.;.;.;.;.;.;.;.
Vest4		0.14
MVP		0.38
MPC		0.045
ClinPred		0.0029	T
GERP RS		1.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.7
Varity_R		0.035
gMVP		0.12

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: rs78104547; hg19: chr9-140611140;