rs767415197

Positions:

• 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.2533del​(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 (★). Synonymous variant affecting the same amino acid position (i.e. R845R) has been classified as Likely benign. 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/exons	MANE	UniProt
KMT2D	NM_003482.4	c.2533del	p.Arg845GlyfsTer85	frameshift_variant	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.2533del	p.Arg845GlyfsTer85	frameshift_variant	11/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.2533del	p.Arg845GlyfsTer85	frameshift_variant	11/56			P4
KMT2D	ENST00000685166.1	c.2533del	p.Arg845GlyfsTer85	frameshift_variant	10/54			A2
KMT2D	ENST00000692637.1	c.2533del	p.Arg845GlyfsTer85	frameshift_variant	10/54			A2

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2017

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). This variant has not been reported in the literature in individuals with KMT2D-related disease. This variant is not present in population databases (ExAC no frequency). 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. -

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;