NM_003482.4:c.1300delC

Variant names:

• chr12-49052382-AG-A
• rs398123715
• NM_003482.4:c.1300delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003482.4(KMT2D):​c.1300delC​(p.Leu434fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,389,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.30
• Publications: 4 publications found

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]

KMT2D Gene-Disease associations (from GenCC):

• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 12-49052382-AG-A is Pathogenic according to our data. Variant chr12-49052382-AG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.1300delC	p.Leu434fs	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.1300delC	p.Leu434fs	frameshift_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1389530 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 682826

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31286

American (AMR) AF: 0.0000279 AC: 1 AN: 35800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39132

South Asian (SAS) AF: 0.00 AC: 0 AN: 73678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5396

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075948

Other (OTH) AF: 0.00 AC: 0 AN: 57144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:1

Jan 13, 2023

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Pathogenic:1

Jun 01, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1300delC pathogenic variant in the KMT2D gene has been reported previously in association with Kabuki syndrome (Miyake et al., 2013). The c.1300delC variant causes a frameshift starting with codon Leucine 434, which changes this amino acid to a premature Stop codon, denoted p.Leu434Ter. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1300delC variant was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1300delC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs398123715; hg19: chr12-49446165; COSMIC: COSV56482677;