chr9-137814350-CTGGAAGACGTAGTTGTGACTGGGAGGGGAAATGGAAGGCCTGTGCCTGCACGTCTGACCCCCCGGCGCCTCTCTTCTCAGTACTGCGTGTGCATCGACGACTGCTCCTCCAGCAACTGCATGTGCGGCCAGCT-C

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: G2P, Ambry Genetics, 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EHMT1	NM_024757.5	c.3181-80_3233del	p.Tyr1061fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 22 of 27	ENST00000460843.6	NP_079033.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EHMT1	ENST00000460843.6	c.3181-80_3233del	p.Tyr1061fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 22 of 27	5	NM_024757.5	ENSP00000417980.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kleefstra syndrome 1 Pathogenic:1 Other:1

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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Computational scores

Source: dbNSFP v4.3

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;