rs62021460

Positions:

• chr15-89652935-A-C

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.-5T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,507,096 control chromosomes in the GnomAD database, including 2,058 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (149 hom., cov: 33)
  • Exomes 𝑓: 0.051 (1909 hom.)
• Consequence: KIF7 NM_198525.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.362

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-89652935-A-C is Benign according to our data. Variant chr15-89652935-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 138059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89652935-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0879 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.-5T>G		5_prime_UTR_variant	2/19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.-5T>G		5_prime_UTR_variant	2/19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000445906.1	n.-5T>G		non_coding_transcript_exon_variant	2/5	1		ENSP00000395906.1
KIF7	ENST00000445906.1	n.-5T>G		5_prime_UTR_variant	2/5	1		ENSP00000395906.1
KIF7	ENST00000696512.1	c.119T>G	p.Leu40Arg	missense_variant	2/19			ENSP00000512678.1

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6117 AN: 152146 Hom.: 148 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0377

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0538

Gnomad OTH AF: 0.0397

GnomAD3 exomes AF: 0.0483 AC: 5738 AN: 118826 Hom.: 173 AF XY: 0.0476 AC XY: 3025 AN XY: 63588

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0600

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.0310

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0541

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0509 AC: 68952 AN: 1354832 Hom.: 1909 Cov.: 34 AF XY: 0.0506 AC XY: 33574 AN XY: 663094

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.0363

Gnomad4 ASJ exome AF: 0.0588

Gnomad4 EAS exome AF: 0.0878

Gnomad4 SAS exome AF: 0.0334

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.0529

Gnomad4 OTH exome AF: 0.0453

GnomAD4 genome AF: 0.0402 AC: 6119 AN: 152264 Hom.: 149 Cov.: 33 AF XY: 0.0394 AC XY: 2935 AN XY: 74458

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.0377

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.0948

Gnomad4 SAS AF: 0.0330

Gnomad4 FIN AF: 0.0325

Gnomad4 NFE AF: 0.0538

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0481 Hom.: 53

Bravo AF: 0.0397

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Acrocallosal syndrome Benign:1

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	11
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs62021460; hg19: chr15-90196166;