rs116823950

chr15-89642262-C-Achr15-89642262-C-Gchr15-89642262-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_198525.3(KIF7):c.2335G>T(p.Glu779Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000686 in 1,458,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E779E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIF7 NM_198525.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05

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 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.2335G>T	p.Glu779Ter	stop_gained	11/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.2335G>T	p.Glu779Ter	stop_gained	11/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1	c.2458G>T	p.Glu820Ter	stop_gained	11/19			A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245690 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133742

Gnomad AFR exome AF: 0.0000636

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458094 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725556

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A
Vest4		0.88
GERP RS		4.9

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: rs116823950; hg19: chr15-90185493;