15-89629547-G-C

Variant names:

• chr15-89629547-G-C
• rs142032413
• NM_198525.3:c.3345C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1115L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 32)
  • Exomes 𝑓: 0.019 (336 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 2.12
• Publications: 13 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 129415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3	c.3345C>G	p.His1115Gln	missense_variant	Exon 17 of 19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.3345C>G	p.His1115Gln	missense_variant	Exon 17 of 19	5	NM_198525.3	ENSP00000377934.3

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2356 AN: 152164 Hom.: 29 Cov.: 32

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

GnomAD2 exomes AF: 0.0160 AC: 3944 AN: 247252 AF XY: 0.0162

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 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.: 37 AF XY: 0.0191 AC XY: 13821 AN XY: 724896

African (AFR) AF: 0.00284 AC: 95 AN: 33478

American (AMR) AF: 0.00387 AC: 173 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 338 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00517 AC: 446 AN: 86258

European-Finnish (FIN) AF: 0.0426 AC: 2052 AN: 48208

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0218 AC: 24274 AN: 1111946

Other (OTH) AF: 0.0157 AC: 948 AN: 60346

GnomAD4 genome AF: 0.0155 AC: 2356 AN: 152282 Hom.: 29 Cov.: 32 AF XY: 0.0157 AC XY: 1172 AN XY: 74466

African (AFR) AF: 0.00380 AC: 158 AN: 41560

American (AMR) AF: 0.00536 AC: 82 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4826

European-Finnish (FIN) AF: 0.0485 AC: 515 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1508 AN: 68020

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.0103 Hom.: 2

Bravo AF: 0.0117

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0240 AC: 206

ExAC AF: 0.0168 AC: 2045

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0192

EpiControl AF: 0.0185

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2014

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. -

Jan 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF7: BS1, BS2 -

Acrocallosal syndrome Benign:2

Feb 03, 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: Likely 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). 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

Feb 01, 2020

Miller Scoliosis Laboratory, University of Colorado Anschutz Medical Campus

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

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

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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

Oct 05, 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.19
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.055	T
Polyphen		0.97	D
Vest4		0.18
MutPred		0.21		Gain of disorder (P = 0.0809);
MPC		0.11
ClinPred		0.016	T
GERP RS		5.1
Varity_R		0.52
gMVP		0.20
Mutation Taster		=79/21	polymorphism (auto)

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

Other links and lift over

dbSNP: rs142032413; hg19: chr15-90172778; COSMIC: COSV99076305; COSMIC: COSV99076305;