9-137717054-C-G

Variant names:

• chr9-137717054-C-G
• rs774693715
• NM_024757.5:c.514C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024757.5(EHMT1):​c.514C>G​(p.Pro172Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P172L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55
• Publications: 2 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, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20615709).

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.514C>G	p.Pro172Ala	missense	Exon 3 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.514C>G	p.Pro172Ala	missense	Exon 3 of 27	NP_001341192.1
	EHMT1	NM_001354259.2		c.421C>G	p.Pro141Ala	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.514C>G	p.Pro172Ala	missense	Exon 3 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.514C>G	p.Pro172Ala	missense	Exon 3 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.514C>G	p.Pro172Ala	missense	Exon 3 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 244812 AF XY: 0.00

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: 0.0000468

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454878 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722808

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86100

European-Finnish (FIN) AF: 0.0000385 AC: 2 AN: 51926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107964

Other (OTH) AF: 0.00 AC: 0 AN: 60060

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.073
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.46	T
Polyphen		0.71	P
Vest4		0.23
MutPred		0.11		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.45
MPC		0.045
ClinPred		0.17	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.027
Mutation Taster		=92/8	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: rs774693715; hg19: chr9-140611506;