15-89633852-C-T

Position:

• chr15-89633852-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198525.3(KIF7):​c.2426G>A​(p.Arg809Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.16

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13384756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF7	NM_198525.3	c.2426G>A	p.Arg809Gln	missense_variant	12/19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8	c.2426G>A	p.Arg809Gln	missense_variant	12/19	5	NM_198525.3	ENSP00000377934	P2
KIF7	ENST00000696512.1	c.2549G>A	p.Arg850Gln	missense_variant	12/19			ENSP00000512678	A2

Frequencies

GnomAD3 genomes AF: 0.000144 AC: 22 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 250998 Hom.: 0 AF XY: 0.0000958 AC XY: 13 AN XY: 135714

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461434 Hom.: 0 Cov.: 34 AF XY: 0.0000481 AC XY: 35 AN XY: 727038

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74396

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Acrocallosal syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 809 of the KIF7 protein (p.Arg809Gln). This variant is present in population databases (rs758378987, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with KIF7-related conditions. ClinVar contains an entry for this variant (Variation ID: 317355). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KIF7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2022

The c.2426G>A (p.R809Q) alteration is located in exon 12 (coding exon 11) of the KIF7 gene. This alteration results from a G to A substitution at nucleotide position 2426, causing the arginine (R) at amino acid position 809 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.67	N
MutationTaster	Benign	0.93	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Benign	0.16	T
Sift4G	Benign	0.18	T
Polyphen		0.85	P
Vest4		0.61
MVP		0.40
MPC		0.049
ClinPred		0.063	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.066

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758378987; hg19: chr15-90177083;