NM_024757.5:c.16G>C

Variant names:

• chr9-137619044-G-C
• rs890540301
• NM_024757.5:c.16G>C

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.16G>C​(p.Ala6Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 146,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. A6T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000014 (0 hom., cov: 31)
• Consequence: EHMT1 NM_024757.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.937
• 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]

ENSG00000283411 (HGNC:):

ARRDC1-AS1 (HGNC:23395): (ARRDC1 antisense RNA 1) This transcribed locus is thought to be non-coding. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

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=0.16498303).

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.16G>C	p.Ala6Pro	missense	Exon 1 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.16G>C	p.Ala6Pro	missense	Exon 1 of 27	NP_001341192.1
	EHMT1	NM_001145527.2		c.16G>C	p.Ala6Pro	missense	Exon 1 of 16	NP_001138999.1	Q9H9B1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.16G>C	p.Ala6Pro	missense	Exon 1 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.16G>C	p.Ala6Pro	missense	Exon 1 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.16G>C	p.Ala6Pro	missense	Exon 1 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000304

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 14

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146082 Hom.: 0 Cov.: 31 AF XY: 0.0000141 AC XY: 1 AN XY: 71018

African (AFR) AF: 0.00 AC: 0 AN: 40766

American (AMR) AF: 0.00 AC: 0 AN: 14714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5084

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000304 AC: 2 AN: 65764

Other (OTH) AF: 0.00 AC: 0 AN: 2008

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.35	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.94
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.046
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.16	T
Polyphen		0.072	B
Vest4		0.15
MutPred		0.19		Gain of loop (P = 0.0045)
MVP		0.38
MPC		0.057
ClinPred		0.11	T
GERP RS		0.31
PromoterAI		0.00050	Neutral
Varity_R		0.089
gMVP		0.074
Mutation Taster		=89/11	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: rs890540301; hg19: chr9-140513496;