9-137717066-C-G

Variant names:

• chr9-137717066-C-G
• rs34704821
• NM_024757.5:c.526C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_024757.5(EHMT1):​c.526C>G​(p.Pro176Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000687 in 1,455,402 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P176S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.52
• Publications: 8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0965648).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.526C>G	p.Pro176Ala	missense	Exon 3 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.526C>G	p.Pro176Ala	missense	Exon 3 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.433C>G	p.Pro145Ala	missense	Exon 2 of 16	NP_001341188.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.526C>G	p.Pro176Ala	missense	Exon 3 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.526C>G	p.Pro176Ala	missense	Exon 3 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.526C>G	p.Pro176Ala	missense	Exon 3 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000687 AC: 10 AN: 1455402 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723082

African (AFR) AF: 0.0000601 AC: 2 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26012

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1108256

Other (OTH) AF: 0.0000166 AC: 1 AN: 60076

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 9

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Kleefstra syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.8
DANN	Benign	0.79
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.065
Sift	Benign	0.044	D
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.25
MutPred		0.077		Loss of loop (P = 0.0203)
MVP		0.24
MPC		0.045
ClinPred		0.091	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.042
Mutation Taster		=95/5	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: rs34704821; hg19: chr9-140611518; COSMIC: COSV107407138; COSMIC: COSV107407138;