rs1554896943

Variant names:

• chr9-137814350-CTGGAAGACGTAGTTGTGACTGGGAGGGGAAATGGAAGGCCTGTGCCTGCACGTCTGACCCCCCGGCGCCTCTCTTCTCAGTACTGCGTGTGCATCGACGACTGCTCCTCCAGCAACTGCATGTGCGGCCAGCT-C
• rs1554896943
• NM_024757.5:c.3181-80_3233del

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_024757.5(EHMT1):​c.3181-80_3233del​(p.Tyr1061fs) variant causes a frameshift, splice acceptor, 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y1061Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EHMT1 NM_024757.5 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.214
• 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]

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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-137814350-CTGGAAGACGTAGTTGTGACTGGGAGGGGAAATGGAAGGCCTGTGCCTGCACGTCTGACCCCCCGGCGCCTCTCTTCTCAGTACTGCGTGTGCATCGACGACTGCTCCTCCAGCAACTGCATGTGCGGCCAGCT-C is Pathogenic according to our data. Variant chr9-137814350-CTGGAAGACGTAGTTGTGACTGGGAGGGGAAATGGAAGGCCTGTGCCTGCACGTCTGACCCCCCGGCGCCTCTCTTCTCAGTACTGCGTGTGCATCGACGACTGCTCCTCCAGCAACTGCATGTGCGGCCAGCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 41267.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.3181-80_3233del	p.Tyr1061fs	frameshift splice_acceptor splice_region intron	Exon 22 of 27	NP_079033.4
	EHMT1	NM_001354263.2		c.3160-80_3212del	p.Tyr1054fs	frameshift splice_acceptor splice_region intron	Exon 22 of 27	NP_001341192.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EHMT1	ENST00000460843.6	TSL:5 MANE Select	c.3181-80_3233del	p.Tyr1061fs	frameshift splice_acceptor splice_region intron	Exon 22 of 27	ENSP00000417980.1	Q9H9B1-1
	EHMT1	ENST00000896765.1		c.3253-80_3305del	p.Tyr1085fs	frameshift splice_acceptor splice_region intron	Exon 23 of 28	ENSP00000566824.1
	EHMT1	ENST00000896763.1		c.3157-80_3209del	p.Tyr1053fs	frameshift splice_acceptor splice_region intron	Exon 22 of 27	ENSP00000566822.1

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: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554896943; hg19: chr9-140708802;