rs553968087

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198525.3(KIF7):​c.1177G>T​(p.Gly393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,132,710 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 3 hom., cov: 32)
Exomes 𝑓: 0.00034 ( 6 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

1
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 2.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.003365159).
BP6
Variant 15-89648521-C-A is Benign according to our data. Variant chr15-89648521-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283923.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3, not_provided=1, Benign=1}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000422 (62/146944) while in subpopulation SAS AF= 0.0104 (50/4816). AF 95% confidence interval is 0.00809. There are 3 homozygotes in gnomad4. There are 43 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF7NM_198525.3 linkc.1177G>T p.Gly393Cys missense_variant 5/19 ENST00000394412.8 NP_940927.2 Q2M1P5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF7ENST00000394412.8 linkc.1177G>T p.Gly393Cys missense_variant 5/195 NM_198525.3 ENSP00000377934.3 Q2M1P5
KIF7ENST00000445906.1 linkn.*836G>T non_coding_transcript_exon_variant 5/51 ENSP00000395906.1 F8WD21
KIF7ENST00000445906.1 linkn.*836G>T 3_prime_UTR_variant 5/51 ENSP00000395906.1 F8WD21
KIF7ENST00000696512.1 linkc.1300G>T p.Gly434Cys missense_variant 5/19 ENSP00000512678.1 A0A8Q3SIQ8

Frequencies

GnomAD3 genomes
AF:
0.000409
AC:
60
AN:
146856
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000489
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000195
Gnomad SAS
AF:
0.00995
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000106
Gnomad OTH
AF:
0.000986
GnomAD3 exomes
AF:
0.00211
AC:
5
AN:
2370
Hom.:
0
AF XY:
0.00324
AC XY:
5
AN XY:
1542
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:
0.0167
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000338
AC:
333
AN:
985766
Hom.:
6
Cov.:
29
AF XY:
0.000477
AC XY:
224
AN XY:
469190
show subpopulations
Gnomad4 AFR exome
AF:
0.0000554
Gnomad4 AMR exome
AF:
0.000227
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00876
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000456
Gnomad4 OTH exome
AF:
0.000675
GnomAD4 genome
AF:
0.000422
AC:
62
AN:
146944
Hom.:
3
Cov.:
32
AF XY:
0.000601
AC XY:
43
AN XY:
71558
show subpopulations
Gnomad4 AFR
AF:
0.0000487
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000196
Gnomad4 SAS
AF:
0.0104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000106
Gnomad4 OTH
AF:
0.000978
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.000102
ExAC
AF:
0.00228
AC:
12

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 27, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Oct 09, 2015- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024KIF7: BS2 -
Acrocallosal syndrome Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 24, 2022This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 393 of the KIF7 protein (p.Gly393Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KIF7-related conditions. ClinVar contains an entry for this variant (Variation ID: 283923). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KIF7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 16, 2021This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Acrocallosal syndrome;C2931104:Hydrolethalus syndrome Other:1
not provided, no classification providedphenotyping onlyGenomeConnect - Invitae Patient Insights Network-Variant interpreted as Uncertain significance and reported on 02-25-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
15
DANN
Benign
0.71
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.059
N
LIST_S2
Benign
0.36
T
MetaRNN
Benign
0.0034
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.20
N
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.17
Sift
Benign
0.13
T
Sift4G
Benign
0.066
T
Polyphen
0.0
B
Vest4
0.16
MutPred
0.27
Gain of helix (P = 0.0128);
MVP
0.35
MPC
0.018
ClinPred
0.032
T
GERP RS
1.5
Varity_R
0.11
gMVP
0.38

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

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

Other links and lift over

dbSNP: rs553968087; hg19: chr15-90191752; API