15-89629561-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_198525.3(KIF7):​c.3331C>T​(p.Arg1111Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000112 in 1,606,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

KIF7
NM_198525.3 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.17
Variant links:
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]
TICRR (HGNC:28704): (TOPBP1 interacting checkpoint and replication regulator) Enables chromatin binding activity. Involved in regulation of DNA-dependent DNA replication initiation. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 15-89629561-G-A is Pathogenic according to our data. Variant chr15-89629561-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89629561-G-A is described in Lovd as [Pathogenic]. Variant chr15-89629561-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF7NM_198525.3 linkuse as main transcriptc.3331C>T p.Arg1111Ter stop_gained 17/19 ENST00000394412.8 NP_940927.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF7ENST00000394412.8 linkuse as main transcriptc.3331C>T p.Arg1111Ter stop_gained 17/195 NM_198525.3 ENSP00000377934 P2
TICRRENST00000561095.1 linkuse as main transcriptc.*228G>A 3_prime_UTR_variant, NMD_transcript_variant 4/41 ENSP00000453922
KIF7ENST00000696512.1 linkuse as main transcriptc.3454C>T p.Arg1152Ter stop_gained 17/19 ENSP00000512678 A2
KIF7ENST00000677187.1 linkuse as main transcriptn.1005C>T non_coding_transcript_exon_variant 5/7

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000408
AC:
1
AN:
245338
Hom.:
0
AF XY:
0.00000750
AC XY:
1
AN XY:
133318
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1454266
Hom.:
0
Cov.:
37
AF XY:
0.00000967
AC XY:
7
AN XY:
723860
show subpopulations
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:
0.0000126
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152156
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000332
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Acrocallosal syndrome Pathogenic:5
Pathogenic, criteria provided, single submitterresearchRare Disease Group, Clinical Genetics, Karolinska InstitutetMar 12, 2019- -
Pathogenic, criteria provided, single submitterresearchUW Hindbrain Malformation Research Program, University of WashingtonFeb 23, 2015- -
Pathogenic, criteria provided, single submitterclinical testingPathology and Clinical Laboratory Medicine, King Fahad Medical City-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 23, 2022This premature translational stop signal has been observed in individual(s) with clinical features of KIF7-related conditions (PMID: 23125460, 27081521). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217670). This variant is present in population databases (no rsID available, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg1111*) in the KIF7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIF7 are known to be pathogenic (PMID: 19666503, 21552264, 21633164, 26648833). -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterSep 22, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
48
DANN
Uncertain
1.0
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A
Vest4
0.94
GERP RS
4.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778139192; hg19: chr15-90172792; COSMIC: COSV51546453; COSMIC: COSV51546453; API