rs149814240

Positions:

• chr15-89645930-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_198525.3(KIF7):​c.1885G>A​(p.Glu629Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,613,772 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (45 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0940

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034671128).
• BP6: Variant 15-89645930-C-T is Benign according to our data. Variant chr15-89645930-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 263139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89645930-C-T is described in Lovd as [Benign]. Variant chr15-89645930-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 7 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.1885G>A	p.Glu629Lys	missense_variant	8/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.1885G>A	p.Glu629Lys	missense_variant	8/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1	c.2008G>A	p.Glu670Lys	missense_variant	8/19			A2

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 766 AN: 152190 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00813

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00531 AC: 1334 AN: 251068 Hom.: 13 AF XY: 0.00510 AC XY: 692 AN XY: 135736

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00427 AC: 6244 AN: 1461464 Hom.: 45 Cov.: 33 AF XY: 0.00436 AC XY: 3170 AN XY: 727080

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0162

Gnomad4 NFE exome AF: 0.00447

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152308 Hom.: 7 Cov.: 32 AF XY: 0.00524 AC XY: 390 AN XY: 74468

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0163

Gnomad4 NFE AF: 0.00813

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00615 Hom.: 11

Bravo AF: 0.00264

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00592 AC: 719

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2017	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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2022	- -

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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KIF7: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Acrocallosal syndrome Benign:2

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Acrocallosal syndrome;C1846722:Multiple epiphyseal dysplasia, Al-Gazali type;C3279899:Hydrolethalus syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.0
DANN	Benign	0.57
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.77	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.12
Sift	Benign	0.61	T
Sift4G	Benign	0.81	T
Polyphen		0.018	B
Vest4		0.21
MVP		0.38
MPC		0.019
ClinPred		0.018	T
GERP RS		1.7
Varity_R		0.045
gMVP		0.40

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: rs149814240; hg19: chr15-90189161;