rs3803530

Positions:

• chr15-89632842-C-A

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.2873G>T​(p.Ser958Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,605,504 control chromosomes in the GnomAD database, including 253,262 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20936 hom., cov: 31)
  • Exomes 𝑓: 0.56 (232326 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.13

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 (MetaRNN=2.8204651E-5).
• BP6: Variant 15-89632842-C-A is Benign according to our data. Variant chr15-89632842-C-A is described in ClinVar as [Benign]. Clinvar id is 96651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89632842-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.2873G>T	p.Ser958Ile	missense_variant	14/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.2873G>T	p.Ser958Ile	missense_variant	14/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1	c.2996G>T	p.Ser999Ile	missense_variant	14/19			A2
KIF7	ENST00000677187.1	n.547G>T		non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79003 AN: 151658 Hom.: 20918 Cov.: 31

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.453

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.509

GnomAD3 exomes AF: 0.515 AC: 124854 AN: 242292 Hom.: 33198 AF XY: 0.520 AC XY: 68259 AN XY: 131198

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.541

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.489

Gnomad FIN exome AF: 0.604

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.521

GnomAD4 exome AF: 0.562 AC: 816529 AN: 1453728 Hom.: 232326 Cov.: 65 AF XY: 0.560 AC XY: 404995 AN XY: 723106

Gnomad4 AFR exome AF: 0.444

Gnomad4 AMR exome AF: 0.416

Gnomad4 ASJ exome AF: 0.543

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.496

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.586

Gnomad4 OTH exome AF: 0.537

GnomAD4 genome AF: 0.521 AC: 79059 AN: 151776 Hom.: 20936 Cov.: 31 AF XY: 0.519 AC XY: 38523 AN XY: 74220

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.453

Gnomad4 ASJ AF: 0.537

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.471

Gnomad4 FIN AF: 0.612

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.509

Alfa AF: 0.560 Hom.: 34176

Bravo AF: 0.505

TwinsUK AF: 0.585 AC: 2168

ALSPAC AF: 0.581 AC: 2240

ESP6500AA AF: 0.466 AC: 2051

ESP6500EA AF: 0.574 AC: 4933

ExAC AF: 0.523 AC: 63524

Asia WGS AF: 0.413 AC: 1440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

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	Eurofins Ntd Llc (ga)	Mar 06, 2013	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Acrocallosal syndrome Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.084
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.000028	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.29	N
MutationTaster	Benign	0.041	P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.098
Sift	Benign	0.28	T
Sift4G	Benign	0.32	T
Polyphen		0.0030	B
Vest4		0.084
MPC		0.021
ClinPred		1.0	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.15

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: rs3803530; hg19: chr15-90176073; COSMIC: COSV51539255; COSMIC: COSV51539255;