rs774073055

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_198525.3(KIF7):c.2654C>T(p.Ala885Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,600,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A885E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.01

Variant links:

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]

KIF7 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31936264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF7	NM_198525.3 linkuse as main transcript	c.2654C>T	p.Ala885Val	missense_variant	13/19	ENST00000394412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
KIF7	ENST00000394412.8 linkuse as main transcript	c.2654C>T	p.Ala885Val	missense_variant	13/19	5	NM_198525.3	P2
KIF7	ENST00000696512.1 linkuse as main transcript	c.2777C>T	p.Ala926Val	missense_variant	13/19			A2
KIF7	ENST00000677187.1 linkuse as main transcript	n.328C>T		non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000216

AC:

AN:

231516

Hom.:

AF XY:

0.0000319

AC XY:

AN XY:

125322

show subpopulations

Gnomad AFR exome

AF:

0.0000670

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000104

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000950

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1448508

Hom.:

Cov.:

AF XY:

0.0000167

AC XY:

AN XY:

719948

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000827

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000992

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2023

The c.2654C>T (p.A885V) alteration is located in exon 13 (coding exon 12) of the KIF7 gene. This alteration results from a C to T substitution at nucleotide position 2654, causing the alanine (A) at amino acid position 885 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Acrocallosal syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2022

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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF7 protein function. ClinVar contains an entry for this variant (Variation ID: 531995). This variant has not been reported in the literature in individuals affected with KIF7-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 885 of the KIF7 protein (p.Ala885Val). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.039

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.23

Sift

Benign

0.083

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.35

MutPred

0.20

Loss of ubiquitination at K880 (P = 0.0589);

MVP

0.75

MPC

0.020

ClinPred

0.29

GERP RS

5.0

Varity_R

0.30

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over