rs1555188379

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003482.4(KMT2D):​c.11944C>T​(p.Arg3982Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

KMT2D
NM_003482.4 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 2.28
Variant links:
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]

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ACMG classification

Classification made for transcript

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 12-49032761-G-A is Pathogenic according to our data. Variant chr12-49032761-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49032761-G-A is described in Lovd as [Pathogenic]. Variant chr12-49032761-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2DNM_003482.4 linkuse as main transcriptc.11944C>T p.Arg3982Ter stop_gained 40/55 ENST00000301067.12 NP_003473.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KMT2DENST00000301067.12 linkuse as main transcriptc.11944C>T p.Arg3982Ter stop_gained 40/555 NM_003482.4 ENSP00000301067 A2O14686-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
47
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Kabuki syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 25, 2021This variant has been observed in individual(s) with Kabuki syndrome (PMID: 21280141, 30107592). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 520944). 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 is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg3982*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. -
Kabuki syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingAutoinflammatory diseases unit, CHU de MontpellierJul 09, 2019- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsFeb 08, 2016- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMar 01, 2024Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21280141, 27302555, 23913813, 30107592, Fan2020[Article]) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
39
DANN
Uncertain
0.99
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.89
D
MutationTaster
Benign
1.0
A
Vest4
0.77
GERP RS
4.8

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555188379; hg19: chr12-49426544; COSMIC: COSV56450787; COSMIC: COSV56450787; API