rs201251064

Positions:

• chr15-89642418-G-A
• chr15-89642418-G-C
• chr15-89642418-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_198525.3(KIF7):​c.2192-13C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,579,596 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (14 hom.)
• Consequence: KIF7 NM_198525.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -0.556

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-89642418-G-A is Benign according to our data. Variant chr15-89642418-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263141.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr15-89642418-G-A is described in Lovd as [Likely_benign]. Variant chr15-89642418-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.2192-13C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.2192-13C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_198525.3	P2
KIF7	ENST00000696512.1	c.2315-13C>T		splice_polypyrimidine_tract_variant, intron_variant				A2

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 151998 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000701

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000774

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00407

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00205 AC: 396 AN: 193190 Hom.: 3 AF XY: 0.00180 AC XY: 189 AN XY: 104886

Gnomad AFR exome AF: 0.000639

Gnomad AMR exome AF: 0.000305

Gnomad ASJ exome AF: 0.00267

Gnomad EAS exome AF: 0.000622

Gnomad SAS exome AF: 0.000632

Gnomad FIN exome AF: 0.00165

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.00237

GnomAD4 exome AF: 0.00376 AC: 5370 AN: 1427480 Hom.: 14 Cov.: 31 AF XY: 0.00364 AC XY: 2571 AN XY: 707088

Gnomad4 AFR exome AF: 0.000550

Gnomad4 AMR exome AF: 0.000466

Gnomad4 ASJ exome AF: 0.00274

Gnomad4 EAS exome AF: 0.000158

Gnomad4 SAS exome AF: 0.000513

Gnomad4 FIN exome AF: 0.00160

Gnomad4 NFE exome AF: 0.00457

Gnomad4 OTH exome AF: 0.00203

GnomAD4 genome AF: 0.00252 AC: 383 AN: 152116 Hom.: 2 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74382

Gnomad4 AFR AF: 0.000699

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000776

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00407

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00308 Hom.: 0

Bravo AF: 0.00229

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	KIF7: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2020	- -

Acrocallosal syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.067
DANN	Benign	0.63

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: rs201251064; hg19: chr15-90185649;