rs752248403

Variant summary

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

The NM_198525.3(KIF7):โ€‹c.2896_2897delGCโ€‹(p.Ala966ProfsTer81) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,550,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (โ˜…โ˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: ๐‘“ 0.000059 ( 0 hom., cov: 34)
Exomes ๐‘“: 0.000019 ( 0 hom. )

Consequence

KIF7
NM_198525.3 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.50
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]

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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 15-89631708-GGC-G is Pathogenic according to our data. Variant chr15-89631708-GGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 30895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89631708-GGC-G is described in Lovd as [Likely_pathogenic]. Variant chr15-89631708-GGC-G is described in Lovd as [Likely_benign]. Variant chr15-89631708-GGC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF7NM_198525.3 linkc.2896_2897delGC p.Ala966ProfsTer81 frameshift_variant, splice_region_variant Exon 15 of 19 ENST00000394412.8 NP_940927.2 Q2M1P5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF7ENST00000394412.8 linkc.2896_2897delGC p.Ala966ProfsTer81 frameshift_variant, splice_region_variant Exon 15 of 19 5 NM_198525.3 ENSP00000377934.3 Q2M1P5
KIF7ENST00000696512.1 linkc.3019_3020delGC p.Ala1007ProfsTer81 frameshift_variant, splice_region_variant Exon 15 of 19 ENSP00000512678.1 A0A8Q3SIQ8
KIF7ENST00000677187.1 linkn.570_571delGC splice_region_variant, non_coding_transcript_exon_variant Exon 3 of 7

Frequencies

GnomAD3 genomes
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000723
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00000646
AC:
1
AN:
154882
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
82476
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000399
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:
0.0000186
AC:
26
AN:
1398702
Hom.:
0
AF XY:
0.0000101
AC XY:
7
AN XY:
689740
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000276
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:
0.0000223
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152214
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.0000718

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Acrocallosal syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 17, 2024This sequence change creates a premature translational stop signal (p.Ala966Profs*81) 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). This variant is present in population databases (rs752248403, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with KIF7-related conditions (PMID: 21552264, 27081521). ClinVar contains an entry for this variant (Variation ID: 30895). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2011- -
Hydrolethalus syndrome 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJun 01, 2011- -
Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 24, 2024- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 09, 2023Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21552264, 27081521, 27894351, 31589614, 34884862) -
Multiple epiphyseal dysplasia, Al-Gazali type Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingDASAMar 05, 2022The c.2896_2897delGC;p.(Ala966Profs*81) is a null frameshift variant (NMD) in the KIF7 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 30895; PMID: 21552264) - PS4. The variant is present at low allele frequencies population databases (rs752248403 โ€“ gnomAD 0.00006457%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
1.0
Position offset: 0
DS_AL_spliceai
1.0
Position offset: 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: rs752248403; hg19: chr15-90174939; API