rs138410949

Positions:

• chr15-89631625-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_198525.3(KIF7):​c.2981A>G​(p.Gln994Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00269 in 1,561,306 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q994H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0028 (8 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:3 B:4
• Conservation: PhyloP100: 3.79

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008629203).
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.2981A>G	p.Gln994Arg	missense_variant	15/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.2981A>G	p.Gln994Arg	missense_variant	15/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1	c.3104A>G	p.Gln1035Arg	missense_variant	15/19			A2
KIF7	ENST00000677187.1	n.655A>G		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152206 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00164 AC: 278 AN: 169278 Hom.: 1 AF XY: 0.00156 AC XY: 141 AN XY: 90458

Gnomad AFR exome AF: 0.000942

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000419

Gnomad FIN exome AF: 0.000506

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00276 AC: 3894 AN: 1408982 Hom.: 8 Cov.: 39 AF XY: 0.00256 AC XY: 1780 AN XY: 696186

Gnomad4 AFR exome AF: 0.000782

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000374

Gnomad4 FIN exome AF: 0.00118

Gnomad4 NFE exome AF: 0.00323

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152324 Hom.: 1 Cov.: 34 AF XY: 0.00196 AC XY: 146 AN XY: 74494

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00263

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00259 Hom.: 1

Bravo AF: 0.00226

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.00164 AC: 14

ExAC AF: 0.000806 AC: 94

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:3 Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23891399, 26092869, 26648833, 21552264, 31322791) -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Uncertain significance, flagged submission	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	KIF7: BP4, BS2 -

Acrocallosal syndrome Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Pathogenic, flagged submission	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Intellectual disability Uncertain:1

Uncertain significance, flagged submission

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.086
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.89	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Benign	0.063	T
Sift4G	Benign	0.26	T
Polyphen		0.0070	B
Vest4		0.20
MVP		0.42
MPC		0.019
ClinPred		0.024	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.10

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: rs138410949; hg19: chr15-90174856;