chr14-58427641-A-C

Position:

• chr14-58427641-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000619416.4(KIAA0586):​c.-39+4A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIAA0586 ENST00000619416.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00006839
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.12

Genes affected

KIAA0586 (HGNC:19960): (KIAA0586) This gene encodes a conserved centrosomal protein that functions in ciliogenesis and responds to hedgehog signaling. Mutations in this gene causes Joubert syndrome 23. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0586	NM_001244189.2	c.9+4A>C		splice_donor_region_variant, intron_variant
KIAA0586	NM_001244190.2	c.-39+4A>C		splice_donor_region_variant, intron_variant
KIAA0586	NM_001244191.2	c.-57+4A>C		splice_donor_region_variant, intron_variant
KIAA0586	NM_001244192.2	c.-57+4A>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0586	ENST00000423743.7	c.-57+4A>C		splice_donor_region_variant, intron_variant		1
KIAA0586	ENST00000619416.4	c.-39+4A>C		splice_donor_region_variant, intron_variant		1		A2
KIAA0586	ENST00000354386.10	c.9+4A>C		splice_donor_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 23;C4225286:Short-rib thoracic dysplasia 14 with polydactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 08, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with KIAA0586-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the KIAA0586 gene. It does not directly change the encoded amino acid sequence of the KIAA0586 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.039
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-58894359;