rs74251725

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198525.3(KIF7):c.3517+6C>T variant causes a splice donor 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. 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_donor_region, intron

Scores

Splicing: ADA: 0.00001589

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.304

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:

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ACMG classification

Classification made for transcript

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	UniProt
KIF7	NM_198525.3 linkuse as main transcript	c.3517+6C>T		splice_donor_region_variant, intron_variant		ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
KIF7	ENST00000394412.8 linkuse as main transcript	c.3517+6C>T	splice_donor_region_variant, intron_variant	5	NM_198525.3	P2
TICRR	ENST00000561095.1 linkuse as main transcript	c.*97-61G>A	intron_variant, NMD_transcript_variant	1
KIF7	ENST00000696512.1 linkuse as main transcript	c.3640+6C>T	splice_donor_region_variant, intron_variant			A2
KIF7	ENST00000677187.1 linkuse as main transcript	n.1191+6C>T	splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39296

AN:

150468

Hom.:

5835

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.326

AC XY:

232044

AN XY:

711154

show subpopulations

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.:

AF XY:

0.261

AC XY:

19194

AN XY:

73460

show subpopulations

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:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

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

Acrocallosal syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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	Genome-Nilou Lab	Aug 19, 2021	- -

Hydrolethalus syndrome 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

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