9-137811547-C-G

Position:

• chr9-137811547-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024757.5(EHMT1):​c.2799C>G​(p.His933Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H933Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.89

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39121997).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.2799C>G	p.His933Gln	missense_variant	19/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.2799C>G	p.His933Gln	missense_variant	19/27	5	NM_024757.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247500 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.22
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.4	D;.;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.013	D;.;.
Sift4G	Uncertain	0.012	D;.;.
Polyphen		0.65	P;.;.
Vest4		0.65
MutPred		0.66		Loss of ubiquitination at K929 (P = 0.2282);.;.;
MVP		0.61
MPC		1.4
ClinPred		0.83	D
GERP RS		-8.2
Varity_R		0.65
gMVP		0.54

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: rs573774002; hg19: chr9-140705999;