15-89632980-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_198525.3(KIF7):c.2735A>G(p.Lys912Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,351,680 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K912K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000019 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.18

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

acrocallosal syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
hydrolethalus syndrome 2
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
hydrolethalus syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
multiple epiphyseal dysplasia, Al-Gazali type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome type 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KIF7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3556634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.2735A>G	p.Lys912Arg	missense_variant	Exon 14 of 19	ENST00000394412.8	NP_940927.2	Q2M1P5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KIF7	ENST00000394412.8 link	c.2735A>G	p.Lys912Arg	missense_variant	Exon 14 of 19	5	NM_198525.3	ENSP00000377934.3	Q2M1P5
KIF7	ENST00000696512.1 link	c.2858A>G	p.Lys953Arg	missense_variant	Exon 14 of 19			ENSP00000512678.1	A0A8Q3SIQ8
KIF7	ENST00000677187.1 link	n.409A>G		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

143472

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000327

AC:

AN:

244852

AF XY:

0.0000301

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000445

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1351680

Hom.:

Cov.:

AF XY:

0.0000149

AC XY:

AN XY:

672428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30218

American (AMR)

AF:

0.0000705

AC:

AN:

42556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22718

East Asian (EAS)

AF:

0.00

AC:

AN:

35792

South Asian (SAS)

AF:

0.00

AC:

AN:

85160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39408

Middle Eastern (MID)

AF:

0.000186

AC:

AN:

5374

European-Non Finnish (NFE)

AF:

0.0000203

AC:

AN:

1036436

Other (OTH)

AF:

0.0000185

AC:

AN:

54018

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

143472

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69678

African (AFR)

AF:

0.00

AC:

AN:

37878

American (AMR)

AF:

0.00

AC:

AN:

14524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

4930

South Asian (SAS)

AF:

0.00

AC:

AN:

4512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65832

Other (OTH)

AF:

0.00

AC:

AN:

1988

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 19, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2735A>G (p.K912R) alteration is located in exon 14 (coding exon 13) of the KIF7 gene. This alteration results from a A to G substitution at nucleotide position 2735, causing the lysine (K) at amino acid position 912 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Feb 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acrocallosal syndrome

Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces lysine with arginine at codon 912 of the KIF7 protein (p.Lys912Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs764430327, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with KIF7-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.054

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

PhyloP100

6.2

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.8

REVEL

Benign

0.14

Sift

Benign

0.21

Sift4G

Benign

0.25

Polyphen

1.0

Vest4

0.52

MutPred

0.28

Loss of ubiquitination at K912 (P = 0.0051);

MVP

0.51

MPC

0.13

ClinPred

0.25

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.32

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over