rs61741227

chr15-89631594-G-A

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.3012C>T(p.Arg1004=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,563,000 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (17 hom., cov: 34)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: KIF7 NM_198525.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.34

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=-0.73).
• BP6: Variant 15-89631594-G-A is Benign according to our data. Variant chr15-89631594-G-A is described in ClinVar as [Benign]. Clinvar id is 129414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89631594-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00777 (1183/152296) while in subpopulation AFR AF= 0.0269 (1117/41570). AF 95% confidence interval is 0.0256. There are 17 homozygotes in gnomad4. There are 557 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.3012C>T	p.Arg1004=	synonymous_variant	15/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.3012C>T	p.Arg1004=	synonymous_variant	15/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1	c.3135C>T	p.Arg1045=	synonymous_variant	15/19			A2
KIF7	ENST00000677187.1	n.686C>T		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 1178 AN: 152178 Hom.: 17 Cov.: 34

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00192 AC: 331 AN: 172230 Hom.: 6 AF XY: 0.00149 AC XY: 137 AN XY: 91908

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.000228

Gnomad EAS exome AF: 0.000155

Gnomad SAS exome AF: 0.000125

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.000791 AC: 1116 AN: 1410704 Hom.: 15 Cov.: 38 AF XY: 0.000759 AC XY: 529 AN XY: 697206

Gnomad4 AFR exome AF: 0.0257

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000512

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000870

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000544

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00777 AC: 1183 AN: 152296 Hom.: 17 Cov.: 34 AF XY: 0.00748 AC XY: 557 AN XY: 74460

Gnomad4 AFR AF: 0.0269

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00389 Hom.: 3

Bravo AF: 0.00855

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2016	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. -

Acrocallosal syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	-0.73
Cadd	Benign	0.10
Dann	Benign	0.92

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: rs61741227; hg19: chr15-90174825;