NM_198525.3:c.1885G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198525.3(KIF7):​c.1885G>A​(p.Glu629Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,613,772 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 7 hom., cov: 32)
Exomes 𝑓: 0.0043 ( 45 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0940
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0034671128).
BP6
Variant 15-89645930-C-T is Benign according to our data. Variant chr15-89645930-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89645930-C-T is described in Lovd as [Benign]. Variant chr15-89645930-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00503 (766/152308) while in subpopulation NFE AF= 0.00813 (553/68008). AF 95% confidence interval is 0.00757. There are 7 homozygotes in gnomad4. There are 390 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 7 AR,Digenic gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF7NM_198525.3 linkc.1885G>A p.Glu629Lys missense_variant Exon 8 of 19 ENST00000394412.8 NP_940927.2 Q2M1P5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF7ENST00000394412.8 linkc.1885G>A p.Glu629Lys missense_variant Exon 8 of 19 5 NM_198525.3 ENSP00000377934.3 Q2M1P5
KIF7ENST00000696512.1 linkc.2008G>A p.Glu670Lys missense_variant Exon 8 of 19 ENSP00000512678.1 A0A8Q3SIQ8

Frequencies

GnomAD3 genomes
AF:
0.00503
AC:
766
AN:
152190
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000362
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00432
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0163
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00813
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00531
AC:
1334
AN:
251068
Hom.:
13
AF XY:
0.00510
AC XY:
692
AN XY:
135736
show subpopulations
Gnomad AFR exome
AF:
0.000369
Gnomad AMR exome
AF:
0.000694
Gnomad ASJ exome
AF:
0.00457
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0164
Gnomad NFE exome
AF:
0.00766
Gnomad OTH exome
AF:
0.00603
GnomAD4 exome
AF:
0.00427
AC:
6244
AN:
1461464
Hom.:
45
Cov.:
33
AF XY:
0.00436
AC XY:
3170
AN XY:
727080
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.000626
Gnomad4 ASJ exome
AF:
0.00643
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0162
Gnomad4 NFE exome
AF:
0.00447
Gnomad4 OTH exome
AF:
0.00339
GnomAD4 genome
AF:
0.00503
AC:
766
AN:
152308
Hom.:
7
Cov.:
32
AF XY:
0.00524
AC XY:
390
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.000361
Gnomad4 AMR
AF:
0.000457
Gnomad4 ASJ
AF:
0.00432
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0163
Gnomad4 NFE
AF:
0.00813
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00615
Hom.:
11
Bravo
AF:
0.00264
TwinsUK
AF:
0.00270
AC:
10
ALSPAC
AF:
0.00234
AC:
9
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00535
AC:
46
ExAC
AF:
0.00592
AC:
719
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00474
EpiControl
AF:
0.00362

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 04, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 23, 2022
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 16, 2017
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:5
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

KIF7: BP4, BS2 -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Clinical Genetics, Academic Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Acrocallosal syndrome Benign:2
Jan 29, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 Benign:1
Oct 22, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
9.0
DANN
Benign
0.57
DEOGEN2
Benign
0.14
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.51
T
MetaRNN
Benign
0.0035
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.7
L
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.78
N
REVEL
Benign
0.12
Sift
Benign
0.61
T
Sift4G
Benign
0.81
T
Polyphen
0.018
B
Vest4
0.21
MVP
0.38
MPC
0.019
ClinPred
0.018
T
GERP RS
1.7
Varity_R
0.045
gMVP
0.40

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: rs149814240; hg19: chr15-90189161; API