rs8030837

Positions:

• chr15-89648432-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_198525.3(KIF7):​c.1266C>G​(p.Leu422Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,111,336 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (8 hom.)
• Consequence: KIF7 NM_198525.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.447

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 15-89648432-G-C is Benign according to our data. Variant chr15-89648432-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 197900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89648432-G-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.447 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0053 (783/147714) while in subpopulation AFR AF= 0.0158 (649/41120). AF 95% confidence interval is 0.0148. There are 12 homozygotes in gnomad4. There are 361 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.1266C>G	p.Leu422Leu	synonymous_variant	5/19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.1266C>G	p.Leu422Leu	synonymous_variant	5/19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000696512.1	c.1389C>G	p.Leu463Leu	synonymous_variant	5/19			ENSP00000512678.1

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 782 AN: 147616 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00357

Gnomad ASJ AF: 0.000587

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.000828

Gnomad OTH AF: 0.00884

GnomAD4 exome AF: 0.00109 AC: 1053 AN: 963622 Hom.: 8 Cov.: 31 AF XY: 0.00109 AC XY: 496 AN XY: 453496

Gnomad4 AFR exome AF: 0.0187

Gnomad4 AMR exome AF: 0.00375

Gnomad4 ASJ exome AF: 0.000342

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000693

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00530 AC: 783 AN: 147714 Hom.: 12 Cov.: 32 AF XY: 0.00501 AC XY: 361 AN XY: 72012

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00357

Gnomad4 ASJ AF: 0.000587

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000829

Gnomad4 OTH AF: 0.00875

Alfa AF: 0.00339 Hom.: 1

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 06, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Acrocallosal syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.9
DANN	Benign	0.80

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: rs8030837; hg19: chr15-90191663;