rs104895327

Positions:

• chr12-109575996-AGGTAGCACTGGCTGTATCCTTGAACTTGAGAACATTCCTCCGGCTTCAACCCCACAGCAATGGGAAAGTGGACCTCAGCTTACCCAACATTGGTATCAAGCGGGCCTGGGATGTGGCCAGGCTTCAGTCACTGGACACAAGCTTTCTG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP3 PP5

The NM_000431.4(MVK):​c.81_226+2del variant causes a splice acceptor, coding sequence change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MVK NM_000431.4 splice_acceptor, coding_sequence
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.30

Genes affected

MVK (HGNC:7530): (mevalonate kinase) This gene encodes the peroxisomal enzyme mevalonate kinase. Mevalonate is a key intermediate, and mevalonate kinase a key early enzyme, in isoprenoid and sterol synthesis. Mevalonate kinase deficiency caused by mutation of this gene results in mevalonic aciduria, a disease characterized psychomotor retardation, failure to thrive, hepatosplenomegaly, anemia and recurrent febrile crises. Defects in this gene also cause hyperimmunoglobulinaemia D and periodic fever syndrome, a disorder characterized by recurrent episodes of fever associated with lymphadenopathy, arthralgia, gastrointestinal dismay and skin rash. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 12-109575996-AGGTAGCACTGGCTGTATCCTTGAACTTGAGAACATTCCTCCGGCTTCAACCCCACAGCAATGGGAAAGTGGACCTCAGCTTACCCAACATTGGTATCAAGCGGGCCTGGGATGTGGCCAGGCTTCAGTCACTGGACACAAGCTTTCTG-A is Pathogenic according to our data. Variant chr12-109575996-AGGTAGCACTGGCTGTATCCTTGAACTTGAGAACATTCCTCCGGCTTCAACCCCACAGCAATGGGAAAGTGGACCTCAGCTTACCCAACATTGGTATCAAGCGGGCCTGGGATGTGGCCAGGCTTCAGTCACTGGACACAAGCTTTCTG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MVK	NM_000431.4	c.81_226+2del		splice_acceptor_variant, coding_sequence_variant	3/11	ENST00000228510.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MVK	ENST00000228510.8	c.81_226+2del		splice_acceptor_variant, coding_sequence_variant	3/11	1	NM_000431.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs104895327; hg19: chr12-110013801;