rs1057519595

Positions:

• chr12-49050593-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003482.4(KMT2D):​c.2994del​(p.Met999Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KMT2D NM_003482.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -2.15

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 18 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 12-49050593-TA-T is Pathogenic according to our data. Variant chr12-49050593-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 375634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.2994del	p.Met999Ter	frameshift_variant	12/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.2994del	p.Met999Ter	frameshift_variant	12/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.2994del	p.Met999Ter	frameshift_variant	12/56			P4
KMT2D	ENST00000685166.1	c.2994del	p.Met999Ter	frameshift_variant	11/54			A2
KMT2D	ENST00000692637.1	c.2994del	p.Met999Ter	frameshift_variant	11/54			A2

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151298 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151298 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73876

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	Aug 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Nov 19, 2015	- -

Kabuki syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2019

This sequence change creates a premature translational stop signal (p.Met999*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Kabuki syndrome (PMID: 27353043). ClinVar contains an entry for this variant (Variation ID: 375634). Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057519595; hg19: chr12-49444376; COSMIC: COSV56466748; COSMIC: COSV56466748;