rs138354681

Positions:

chr15-89633777-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_198525.3(KIF7):c.2501A>G(p.Gln834Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,611,624 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0047 ( 24 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 7.94

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]

KIF7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020664513).

BP6

Variant 15-89633777-T-C is Benign according to our data. Variant chr15-89633777-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252807.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=1}. Variant chr15-89633777-T-C is described in Lovd as [Likely_benign]. Variant chr15-89633777-T-C is described in Lovd as [Likely_pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 24 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3 linkuse as main transcript	c.2501A>G	p.Gln834Arg	missense_variant	12/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8 linkuse as main transcript	c.2501A>G	p.Gln834Arg	missense_variant	12/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1 linkuse as main transcript	c.2624A>G	p.Gln875Arg	missense_variant	12/19			A2

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

461

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.000659

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00327

AC:

814

AN:

249166

Hom.:

AF XY:

0.00339

AC XY:

458

AN XY:

134948

show subpopulations

Gnomad AFR exome

AF:

0.000802

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00366

Gnomad FIN exome

AF:

0.000960

Gnomad NFE exome

AF:

0.00469

Gnomad OTH exome

AF:

0.00491

GnomAD4 exome

AF:

0.00466

AC:

6798

AN:

1459256

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

3365

AN XY:

726088

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00208

Gnomad4 ASJ exome

AF:

0.00321

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00368

Gnomad4 FIN exome

AF:

0.00122

Gnomad4 NFE exome

AF:

0.00529

Gnomad4 OTH exome

AF:

0.00532

GnomAD4 genome

AF:

0.00302

AC:

460

AN:

152368

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.000659

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.00292

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00320

AC:

388

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 02, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 08, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 07, 2020	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2021	This variant is associated with the following publications: (PMID: 21552264, 29343940, 28700940) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 12, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KIF7: BS2 -

Acrocallosal syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Nephronophthisis

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Sep 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.24

Sift

Benign

0.034

Sift4G

Benign

0.24

Polyphen

1.0

Vest4

0.67

MVP

0.59

MPC

0.15

ClinPred

0.0038

GERP RS

5.1

Varity_R

0.64

gMVP

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over