chr15-89631593-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_198525.3(KIF7):c.3013G>A(p.Gly1005Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,561,492 control chromosomes in the GnomAD database, including 246,566 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 21072 hom., cov: 34)

Exomes 𝑓: 0.56 ( 225494 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.19

Publications

29 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1864759E-5).

BP6

Variant 15-89631593-C-T is Benign according to our data. Variant chr15-89631593-C-T is described in ClinVar as [Benign]. Clinvar id is 96653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.3013G>A	p.Gly1005Arg	missense_variant	Exon 15 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.3013G>A	p.Gly1005Arg	missense_variant	Exon 15 of 19	5	NM_198525.3	ENSP00000377934.3	Q2M1P5
KIF7	ENST00000696512.1 link	c.3136G>A	p.Gly1046Arg	missense_variant	Exon 15 of 19			ENSP00000512678.1	A0A8Q3SIQ8
KIF7	ENST00000677187.1 link	n.687G>A		non_coding_transcript_exon_variant	Exon 3 of 7

Frequencies

GnomAD3 genomes

AF:

0.522

AC:

79297

AN:

151976

Hom.:

21054

Cov.:

show subpopulations

Gnomad AFR

AF:

0.448

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.453

Gnomad ASJ

AF:

0.538

Gnomad EAS

AF:

0.335

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.614

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.583

Gnomad OTH

AF:

0.511

GnomAD2 exomes

AF:

0.500

AC:

85815

AN:

171570

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.428

Gnomad AMR exome

AF:

0.404

Gnomad ASJ exome

AF:

0.534

Gnomad EAS exome

AF:

0.307

Gnomad FIN exome

AF:

0.604

Gnomad NFE exome

AF:

0.561

Gnomad OTH exome

AF:

0.506

GnomAD4 exome

AF:

0.562

AC:

791872

AN:

1409398

Hom.:

225494

Cov.:

AF XY:

0.560

AC XY:

389975

AN XY:

696490

show subpopulations

African (AFR)

AF:

0.440

AC:

14120

AN:

32056

American (AMR)

AF:

0.410

AC:

15631

AN:

38116

Ashkenazi Jewish (ASJ)

AF:

0.542

AC:

13741

AN:

25362

East Asian (EAS)

AF:

0.303

AC:

11112

AN:

36716

South Asian (SAS)

AF:

0.499

AC:

40074

AN:

80232

European-Finnish (FIN)

AF:

0.608

AC:

29785

AN:

48954

Middle Eastern (MID)

AF:

0.455

AC:

2574

AN:

5658

European-Non Finnish (NFE)

AF:

0.585

AC:

633703

AN:

1084004

Other (OTH)

AF:

0.534

AC:

31132

AN:

58300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

16926

33853

50779

67706

84632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17534

35068

52602

70136

87670

<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:

0.522

AC:

79353

AN:

152094

Hom.:

21072

Cov.:

AF XY:

0.520

AC XY:

38659

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.448

AC:

18602

AN:

41490

American (AMR)

AF:

0.453

AC:

6933

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.538

AC:

1867

AN:

3472

East Asian (EAS)

AF:

0.336

AC:

1727

AN:

5138

South Asian (SAS)

AF:

0.477

AC:

2304

AN:

4826

European-Finnish (FIN)

AF:

0.614

AC:

6502

AN:

10598

Middle Eastern (MID)

AF:

0.521

AC:

152

AN:

292

European-Non Finnish (NFE)

AF:

0.583

AC:

39630

AN:

67964

Other (OTH)

AF:

0.510

AC:

1078

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1951

3902

5852

7803

9754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

692

1384

2076

2768

3460

<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:

0.557

Hom.:

34992

Bravo

AF:

0.505

TwinsUK

AF:

0.585

AC:

2169

ALSPAC

AF:

0.581

AC:

2238

ESP6500AA

AF:

0.461

AC:

2015

ESP6500EA

AF:

0.567

AC:

4847

ExAC

AF:

0.406

AC:

44699

Asia WGS

AF:

0.415

AC:

1447

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acrocallosal syndrome

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hydrolethalus syndrome 2

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Multiple epiphyseal dysplasia, Al-Gazali type

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

8.9

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.090

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.73

MetaRNN

Benign

0.000012

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

PhyloP100

1.2

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.15

REVEL

Benign

0.047

Sift

Benign

0.23

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.065

MutPred

0.052

Gain of MoRF binding (P = 0.0155);

MPC

0.019

ClinPred

0.0052

GERP RS

-0.47

Varity_R

0.068

gMVP

0.21

Mutation Taster

=99/1

polymorphism (auto)

(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