NM_198525.3:c.2815C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_198525.3(KIF7):c.2815C>T(p.Arg939Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000771 in 1,608,984 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R939Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000080 ( 1 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.24

Publications

3 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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.2815C>T	p.Arg939Trp	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.2815C>T	p.Arg939Trp	missense_variant	Exon 14 of 19	5	NM_198525.3	ENSP00000377934.3	Q2M1P5
KIF7	ENST00000696512.1 link	c.2938C>T	p.Arg980Trp	missense_variant	Exon 14 of 19			ENSP00000512678.1	A0A8Q3SIQ8
KIF7	ENST00000677187.1 link	n.489C>T		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes

AF:

0.0000531

AC:

AN:

150726

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000583

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000810

AC:

AN:

246796

AF XY:

0.0000374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.0000530

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000796

AC:

116

AN:

1458146

Hom.:

Cov.:

AF XY:

0.0000868

AC XY:

AN XY:

725480

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.0000448

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.000151

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000729

AC:

AN:

1111716

Other (OTH)

AF:

0.000414

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000530

AC:

AN:

150838

Hom.:

Cov.:

AF XY:

0.0000544

AC XY:

AN XY:

73552

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41136

American (AMR)

AF:

0.00

AC:

AN:

15000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000585

AC:

AN:

5132

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000738

AC:

AN:

67792

Other (OTH)

AF:

0.00

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000577

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2815C>T (p.R939W) alteration is located in exon 14 (coding exon 13) of the KIF7 gene. This alteration results from a C to T substitution at nucleotide position 2815, causing the arginine (R) at amino acid position 939 to be replaced by a tryptophan (W). 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

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jun 12, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Acrocallosal syndrome

Uncertain:1

Oct 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 939 of the KIF7 protein (p.Arg939Trp). This variant is present in population databases (rs142786336, gnomAD 0.04%). 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: 531998). Invitae Evidence 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 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. 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.0

PhyloP100

2.2

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.4

REVEL

Benign

0.18

Sift

Uncertain

0.014

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.71

MVP

0.72

MPC

0.14

ClinPred

0.40

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.71

Mutation Taster

=68/32

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over