9-137710980-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_024757.5(EHMT1):c.35G>T(p.Arg12Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,445,226 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. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.72

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15902841).
• BP6: Variant 9-137710980-G-T is Benign according to our data. Variant chr9-137710980-G-T is described in ClinVar as [Benign]. Clinvar id is 462996.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EHMT1	NM_024757.5	c.35G>T	p.Arg12Met	missense_variant	2/27	ENST00000460843.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EHMT1	ENST00000460843.6	c.35G>T	p.Arg12Met	missense_variant	2/27	5	NM_024757.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000908 AC: 2 AN: 220370 Hom.: 0 AF XY: 0.00000836 AC XY: 1 AN XY: 119656

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: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1445226 Hom.: 0 Cov.: 31 AF XY: 0.00000279 AC XY: 2 AN XY: 717148

Gnomad4 AFR exome AF: 0.0000301

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: 0.00000453

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000250 AC: 3

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Benign	0.92
DEOGEN2	Benign	0.072	T;.;T;.
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;N;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.51	N;N;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.0050	D;D;.;D
Polyphen		0.064	B;B;.;.
Vest4		0.36
MutPred		0.18		Loss of solvent accessibility (P = 0.0022);Loss of solvent accessibility (P = 0.0022);Loss of solvent accessibility (P = 0.0022);.;
MVP		0.48
MPC		0.050
ClinPred		0.28	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs777999570; hg19: chr9-140605432;