chr9-137619031-G-A

Variant names:

• chr9-137619031-G-A
• rs1369831824
• NM_024757.5:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_024757.5(EHMT1):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000121 in 823,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: EHMT1 NM_024757.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 32 codons. Genomic position: 137716634. Lost 0.024 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.3G>A	p.Met1?	start_lost	Exon 1 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.3G>A	p.Met1?	start_lost	Exon 1 of 27	NP_001341192.1
	EHMT1	NM_001145527.2		c.3G>A	p.Met1?	start_lost	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.3G>A	p.Met1?	start_lost	Exon 1 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000896765.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 28	ENSP00000566824.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000121 AC: 1 AN: 823894 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 381008

African (AFR) AF: 0.00 AC: 0 AN: 15576

American (AMR) AF: 0.00 AC: 0 AN: 1086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5176

East Asian (EAS) AF: 0.00 AC: 0 AN: 3662

South Asian (SAS) AF: 0.00 AC: 0 AN: 17020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1612

European-Non Finnish (NFE) AF: 0.00000133 AC: 1 AN: 752178

Other (OTH) AF: 0.00 AC: 0 AN: 27032

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.092	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.72	T
PhyloP100		3.2
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.70
MutPred		1.0		Gain of helix (P = 0.2059)
MVP		0.72
ClinPred		0.74	D
GERP RS		1.5
PromoterAI		-0.51	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.099
Mutation Taster		=16/184	disease causing

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: rs1369831824; hg19: chr9-140513483;