rs750812056

chr15-89631699-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198525.3(KIF7):c.2907G>C(p.Glu969Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,553,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: KIF7 NM_198525.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.364

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052188158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3	c.2907G>C	p.Glu969Asp	missense_variant	15/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF7	ENST00000394412.8	c.2907G>C	p.Glu969Asp	missense_variant	15/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1	c.3030G>C	p.Glu1010Asp	missense_variant	15/19			A2
KIF7	ENST00000677187.1	n.581G>C		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000629 AC: 1 AN: 158876 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 84562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000163

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 25 AN: 1401000 Hom.: 0 Cov.: 38 AF XY: 0.0000203 AC XY: 14 AN XY: 691116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000222

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000902 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 01, 2014

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2017

A variant of uncertain significance has been identified in the KIF7 gene. The E969D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E969D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved in mammals. However, the E969D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.76	N
MutationTaster	Benign	0.51	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.080
Sift	Benign	0.22	T
Sift4G	Benign	0.26	T
Polyphen		0.016	B
Vest4		0.20
MutPred		0.19		Loss of MoRF binding (P = 0.1255);
MVP		0.28
MPC		0.018
ClinPred		0.10	T
GERP RS		1.1
Varity_R		0.053
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: rs750812056; hg19: chr15-90174930;