rs797044465

Positions:

• chr15-89652713-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_198525.3(KIF7):​c.217del​(p.Ala73ProfsTer109) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A73A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: KIF7 NM_198525.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.314

Genes affected

KIF7 (HGNC:30497): (kinesin family member 7) This gene encodes a cilia-associated protein belonging to the kinesin family. This protein plays a role in the sonic hedgehog (SHH) signaling pathway through the regulation of GLI transcription factors. It functions as a negative regulator of the SHH pathway by preventing inappropriate activation of GLI2 in the absence of ligand, and as a positive regulator by preventing the processing of GLI3 into its repressor form. Mutations in this gene have been associated with various ciliopathies. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 15-89652713-GC-G is Pathogenic according to our data. Variant chr15-89652713-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 30900.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.217del	p.Ala73ProfsTer109	frameshift_variant	2/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.217del	p.Ala73ProfsTer109	frameshift_variant	2/19	5	NM_198525.3	P2
KIF7	ENST00000445906.1	c.217del	p.Ala73ProfsTer61	frameshift_variant, NMD_transcript_variant	2/5	1
KIF7	ENST00000696512.1	c.340del	p.Ala114ProfsTer109	frameshift_variant	2/19			A2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 24, 2016

The c.217delG variant in the KIF7 gene has been reported previously in the homozygous state in two related individuals with Joubert syndrome (Dafinger et al., 2011). This variant causes a frameshift starting with codon Alanine 73, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 109 of the new reading frame, denoted p.Ala73ProfsX109. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.217delG variant was not observed in approximately 2300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.217delG as a pathogenic variant. -

Joubert syndrome 12 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs797044465; hg19: chr15-90195944;