chr12-49031186-TG-T

Variant names:

• chr12-49031186-TG-T
• rs587783691
• NM_003482.4:c.13518delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003482.4(KMT2D):​c.13518delC​(p.Ser4507AlafsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2D NM_003482.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.33
• Publications: 2 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 12 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 12-49031186-TG-T is Pathogenic according to our data. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-49031186-TG-T is described in CliVar as Pathogenic. Clinvar id is 158730.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.13518delC	p.Ser4507AlafsTer12	frameshift_variant	Exon 40 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.13518delC	p.Ser4507AlafsTer12	frameshift_variant	Exon 40 of 55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1456210 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 723632

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.00 AC: 0 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108406

Other (OTH) AF: 0.00 AC: 0 AN: 60126

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:1

Oct 10, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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)		0.0		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: rs587783691; hg19: chr12-49424969; COSMIC: COSV56496397;