rs1555186619

Positions:

• chr12-49029399-ACCTGACAT-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_003482.4(KMT2D):​c.14069_14075+1delATGTCAGG​(p.Asp4690fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.86

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49029399-ACCTGACAT-A is Pathogenic according to our data. Variant chr12-49029399-ACCTGACAT-A is described in ClinVar as [Pathogenic]. Clinvar id is 559648.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.14069_14075+1delATGTCAGG	p.Asp4690fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	44/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.14069_14075+1delATGTCAGG	p.Asp4690fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	44/55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Apr 26, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555186619; hg19: chr12-49423182;