rs767415197

Variant names:

• chr12-49051149-CG-C
• rs767415197
• NM_003482.4:c.2533delC

Your query was ambiguous. Multiple possible variants found:

• chr12-49051149-CG-C
• chr12-49051149-CG-CGG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1 PP5_Moderate BS2

The NM_003482.4(KMT2D):​c.2533delC​(p.Arg845GlyfsTer85) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,359,590 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: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: KMT2D NM_003482.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -2.28

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 12-49051149-CG-C is Pathogenic according to our data. Variant chr12-49051149-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 531886.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.2533delC	p.Arg845GlyfsTer85	frameshift_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.2533delC	p.Arg845GlyfsTer85	frameshift_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2	c.2533delC	p.Arg845GlyfsTer85	frameshift_variant	Exon 11 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1	c.2533delC	p.Arg845GlyfsTer85	frameshift_variant	Exon 10 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1	c.2533delC	p.Arg845GlyfsTer85	frameshift_variant	Exon 10 of 54			ENSP00000509666.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000118 AC: 16 AN: 1359590 Hom.: 0 Cov.: 33 AF XY: 0.0000180 AC XY: 12 AN XY: 667472

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000501

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000286

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000123

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome Pathogenic:1

Nov 27, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg845Glyfs*85) 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 not been reported in the literature in individuals with KMT2D-related disease. 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: rs767415197; hg19: chr12-49444932;