chr12-49021873-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_003482.4(KMT2D):c.16522-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_003482.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KMT2D | ENST00000301067.12 | c.16522-1G>A | splice_acceptor_variant, intron_variant | Intron 54 of 54 | 5 | NM_003482.4 | ENSP00000301067.7 | |||
ENSG00000288710 | ENST00000683988.1 | n.493-1G>A | splice_acceptor_variant, intron_variant | Intron 4 of 15 | ENSP00000506939.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
The c.16522-1G>A variant in the KMT2D gene has not been reported previously as a pathogenic variant noras a benign polymorphism, to our knowledge. However, this splice site variant destroys thecanonical splice acceptor site in intron 53 . It is predicted to cause abnormal gene splicing, either leading toan abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal proteinproduct if the message is used for protein translation. The c.16522-1G>A variant was not observed inapproximately 6100 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. While this specificsplice site variant has not been reported, other splice site variants in the KMT2D gene associated withKabuki syndrome have been noted in HGMD (Stenson et al., 2014). Thus, we interpret c.16522-1G>A in KMT2D as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at