rs74251725

Positions:

• chr15-89629369-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_198525.3(KIF7):​c.3517+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 1,583,102 control chromosomes in the GnomAD database, including 82,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5835 hom., cov: 28)
  • Exomes 𝑓: 0.32 (76748 hom.)
• Consequence: KIF7 NM_198525.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001589
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.304

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]

KIF7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-89629369-G-A is Benign according to our data. Variant chr15-89629369-G-A is described in ClinVar as [Benign]. Clinvar id is 129416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89629369-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.3517+6C>T		splice_region_variant, intron_variant		ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.3517+6C>T		splice_region_variant, intron_variant		5	NM_198525.3	ENSP00000377934.3
TICRR	ENST00000561095.1	n.*97-61G>A		intron_variant		1		ENSP00000453922.1
KIF7	ENST00000696512.1	c.3640+6C>T		splice_region_variant, intron_variant				ENSP00000512678.1
KIF7	ENST00000677187.1	n.1191+6C>T		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39296 AN: 150468 Hom.: 5835 Cov.: 28

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.334

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.344

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.298

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.289

GnomAD3 exomes AF: 0.308 AC: 71590 AN: 232426 Hom.: 11588 AF XY: 0.316 AC XY: 39990 AN XY: 126614

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.355

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.324 AC: 463632 AN: 1432522 Hom.: 76748 Cov.: 35 AF XY: 0.326 AC XY: 232044 AN XY: 711154

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.302

Gnomad4 EAS exome AF: 0.340

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.275

Gnomad4 NFE exome AF: 0.330

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.261 AC: 39296 AN: 150580 Hom.: 5835 Cov.: 28 AF XY: 0.261 AC XY: 19194 AN XY: 73460

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.279

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.343

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.329

Gnomad4 OTH AF: 0.287

Alfa AF: 0.306 Hom.: 1458

Bravo AF: 0.254

Asia WGS AF: 0.333 AC: 1153 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Acrocallosal syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hydrolethalus syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Multiple epiphyseal dysplasia, Al-Gazali type Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.4
DANN	Benign	0.79
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs74251725; hg19: chr15-90172600; COSMIC: COSV51544315; COSMIC: COSV51544315;