chr15-89629547-G-C

Position:

chr15-89629547-G-C

Variant summary

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

The NM_198525.3(KIF7):c.3345C>G(p.His1115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,608,834 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 29 hom., cov: 32)

Exomes 𝑓: 0.019 ( 336 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 2.12

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:

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]

TICRR links:

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=0.0075957477).

BP6

Variant 15-89629547-G-C is Benign according to our data. Variant chr15-89629547-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 129415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89629547-G-C is described in Lovd as [Benign]. Variant chr15-89629547-G-C is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0155 (2356/152282) while in subpopulation NFE AF= 0.0222 (1508/68020). AF 95% confidence interval is 0.0212. There are 29 homozygotes in gnomad4. There are 1172 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3 linkuse as main transcript	c.3345C>G	p.His1115Gln	missense_variant	17/19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KIF7	ENST00000394412.8 linkuse as main transcript	c.3345C>G	p.His1115Gln	missense_variant	17/19	5	NM_198525.3	ENSP00000377934	P2
TICRR	ENST00000561095.1 linkuse as main transcript	c.*214G>C		3_prime_UTR_variant, NMD_transcript_variant	4/4	1		ENSP00000453922
KIF7	ENST00000696512.1 linkuse as main transcript	c.3468C>G	p.His1156Gln	missense_variant	17/19			ENSP00000512678	A2
KIF7	ENST00000677187.1 linkuse as main transcript	n.1019C>G		non_coding_transcript_exon_variant	5/7

Frequencies

GnomAD3 genomes

AF:

0.0155

AC:

2356

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00381

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.0485

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0222

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.0160

AC:

3944

AN:

247252

Hom.:

AF XY:

0.0162

AC XY:

2179

AN XY:

134166

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.0147

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00464

Gnomad FIN exome

AF:

0.0470

Gnomad NFE exome

AF:

0.0225

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0195

AC:

28345

AN:

1456552

Hom.:

336

Cov.:

AF XY:

0.0191

AC XY:

13821

AN XY:

724896

show subpopulations

Gnomad4 AFR exome

AF:

0.00284

Gnomad4 AMR exome

AF:

0.00387

Gnomad4 ASJ exome

AF:

0.0129

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00517

Gnomad4 FIN exome

AF:

0.0426

Gnomad4 NFE exome

AF:

0.0218

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0155

AC:

2356

AN:

152282

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1172

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00380

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.0485

Gnomad4 NFE

AF:

0.0222

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.0103

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0240

AC:

206

ExAC

AF:

0.0168

AC:

2045

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0192

EpiControl

AF:

0.0185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2014	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:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	KIF7: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Acrocallosal syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Scoliosis, isolated, susceptibility to, 1

Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Miller Scoliosis Laboratory, University of Colorado Anschutz Medical Campus

Feb 01, 2020

Several affected individuals within a multigenerational family possess the variant in question. Mutations in this gene were also found to cause scoliosis in a zebrafish model. -

Hydrolethalus syndrome 2

Benign:1

Benign, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

May 31, 2018

This variant is interpreted as a Benign, for Hydrolethalus syndrome 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PS3-Moderate => PS3 downgraded in strength to Moderate. BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0076

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.4

MutationTaster

Benign

0.97

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.19

Sift

Uncertain

0.013

Sift4G

Uncertain

0.055

Polyphen

0.97

Vest4

0.18

MutPred

0.21

Gain of disorder (P = 0.0809);

MPC

0.11

ClinPred

0.016

GERP RS

5.1

Varity_R

0.52

gMVP

0.20

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