rs1564509503

Variant names:

• chr9-137619031-GGCCGCCGCCGATGCCGAGGTGAGCAGCGGGGCCGGCGGGGGGCGGCGCGGGGGCGGCGGGCAGCGGCGGAGGCGGCGCGGGGGCGAAGAACCGGGCGGGGCGGCGGCAGGCGGCCGGCGGGCGGGCGGGGCCCCGGGTCCCCCCGCCGCCGCCGCCGCCGCT-G
• rs1564509503
• NM_024757.5:c.13_21+153del

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_024757.5(EHMT1):​c.13_21+153del​(p.Asp5_Glu7del) variant causes a splice donor, conservative inframe deletion, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EHMT1 NM_024757.5 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.67
• 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 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011547344 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 9-137619031-GGCCGCCGCCGATGCCGAGGTGAGCAGCGGGGCCGGCGGGGGGCGGCGCGGGGGCGGCGGGCAGCGGCGGAGGCGGCGCGGGGGCGAAGAACCGGGCGGGGCGGCGGCAGGCGGCCGGCGGGCGGGCGGGGCCCCGGGTCCCCCCGCCGCCGCCGCCGCCGCT-G is Pathogenic according to our data. Variant chr9-137619031-GGCCGCCGCCGATGCCGAGGTGAGCAGCGGGGCCGGCGGGGGGCGGCGCGGGGGCGGCGGGCAGCGGCGGAGGCGGCGCGGGGGCGAAGAACCGGGCGGGGCGGCGGCAGGCGGCCGGCGGGCGGGCGGGGCCCCGGGTCCCCCCGCCGCCGCCGCCGCCGCT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 573983.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	NM_024757.5	MANE Select	c.13_21+153del	p.Asp5_Glu7del	splice_donor conservative_inframe_deletion splice_region intron	Exon 1 of 27	NP_079033.4
	EHMT1	NM_001354259.2		c.-17_-9+153del		splice_region	Exon 1 of 16	NP_001341188.1
	EHMT1	NM_001354612.2		c.-17_-9+153del		splice_region	Exon 1 of 9	NP_001341541.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.13_21+153del	p.Asp5_Glu7del	splice_donor conservative_inframe_deletion splice_region intron	Exon 1 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000462484.5	TSL:1	c.13_21+153del	p.Asp5_Glu7del	splice_donor conservative_inframe_deletion splice_region intron	Exon 1 of 16	ENSP00000417328.1	Q9H9B1-4
	EHMT1	ENST00000630754.2	TSL:3	c.-259_-251+153del		splice_region	Exon 1 of 4	ENSP00000485933.1	A0A0D9SER3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

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
PhyloP100		2.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1564509503; hg19: chr9-140513483;