9-137716838-G-C

Position:

• chr9-137716838-G-C

Variant summary

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

The NM_024757.5(EHMT1):​c.298G>C​(p.Asp100His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.73

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=0.27238697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.298G>C	p.Asp100His	missense_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.298G>C	p.Asp100His	missense_variant	3/27	5	NM_024757.5	ENSP00000417980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;T;T;T;T;T;.;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.8	N;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.019	D;D;D;D;.;.;D;D;.;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.
Vest4		0.65
MutPred		0.19		Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);.;.;.;.;.;
MVP		0.66
MPC		0.31
ClinPred		0.87	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.43

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: rs540121859; hg19: chr9-140611290;