NM_024757.5:c.3883G>T

Variant names:

• chr9-137834939-G-T
• rs775220788
• NM_024757.5:c.3883G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_024757.5(EHMT1):​c.3883G>T​(p.Ala1295Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000734 in 1,361,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1295T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.00
• Publications: 0 publications found

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]

EHMT1 Gene-Disease associations (from GenCC):

• Kleefstra syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Kleefstra syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06557667).
• BP6: Variant 9-137834939-G-T is Benign according to our data. Variant chr9-137834939-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 568691.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.3883G>T	p.Ala1295Ser	missense	Exon 27 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.3862G>T	p.Ala1288Ser	missense	Exon 27 of 27	NP_001341192.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.3883G>T	p.Ala1295Ser	missense	Exon 27 of 27	ENSP00000417980.1
	EHMT1	ENST00000475564.5	TSL:1	n.1607G>T		non_coding_transcript_exon	Exon 4 of 4
	EHMT1	ENST00000494249.5	TSL:1	n.1236G>T		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000895 AC: 1 AN: 111744 AF XY: 0.0000161

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.34e-7 AC: 1 AN: 1361678 Hom.: 0 Cov.: 31 AF XY: 0.00000149 AC XY: 1 AN XY: 671202

African (AFR) AF: 0.00 AC: 0 AN: 30120

American (AMR) AF: 0.00 AC: 0 AN: 29404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22360

East Asian (EAS) AF: 0.00 AC: 0 AN: 35534

South Asian (SAS) AF: 0.0000135 AC: 1 AN: 74248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3938

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068522

Other (OTH) AF: 0.00 AC: 0 AN: 56270

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 1 Benign:1

Apr 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.060	N
PhyloP100		1.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.048
Sift	Uncertain	0.024	D
Sift4G	Benign	0.35	T
Polyphen		0.38	B
Vest4		0.23
MutPred		0.15		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.40
MPC		0.66
ClinPred		0.11	T
GERP RS		3.2
Varity_R		0.063
gMVP		0.46
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs775220788; hg19: chr9-140729391; COSMIC: COSV66044612; COSMIC: COSV66044612;