14-58482712-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001329943.3(KIAA0586):​c.3144G>T​(p.Pro1048Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

KIAA0586
NM_001329943.3 splice_region, synonymous

Scores

2
Splicing: ADA: 0.9999
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.43
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIAA0586NM_001329943.3 linkc.3144G>T p.Pro1048Pro splice_region_variant, synonymous_variant Exon 21 of 31 ENST00000652326.2 NP_001316872.1 A0A494C171

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIAA0586ENST00000652326.2 linkc.3144G>T p.Pro1048Pro splice_region_variant, synonymous_variant Exon 21 of 31 NM_001329943.3 ENSP00000498929.1 A0A494C171

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
7.19e-7
AC:
1
AN:
1390922
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
687854
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000175
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
18
DANN
Benign
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.97
SpliceAI score (max)
0.82
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.82
Position offset: 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: chr14-58949430; API