15-89652736-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_198525.3(KIF7):c.195G>C(p.Ala65Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.904 in 1,551,594 control chromosomes in the GnomAD database, including 636,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A65A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.90 ( 62636 hom., cov: 35)

Exomes 𝑓: 0.90 ( 574049 hom. )

Consequence

KIF7
NM_198525.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -6.59

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 15-89652736-C-G is Benign according to our data. Variant chr15-89652736-C-G is described in ClinVar as Benign. ClinVar VariationId is 129408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-6.59 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.952 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.195G>C	p.Ala65Ala	synonymous_variant	Exon 2 of 19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KIF7	ENST00000394412.8 link	c.195G>C	p.Ala65Ala	synonymous_variant	Exon 2 of 19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000445906.1 link	n.195G>C		non_coding_transcript_exon_variant	Exon 2 of 5	1		ENSP00000395906.1
KIF7	ENST00000696512.1 link	c.318G>C	p.Ala106Ala	synonymous_variant	Exon 2 of 19			ENSP00000512678.1

Frequencies

GnomAD3 genomes

AF:

0.905

AC:

137730

AN:

152204

Hom.:

62589

Cov.:

show subpopulations

Gnomad AFR

AF:

0.960

Gnomad AMI

AF:

0.950

Gnomad AMR

AF:

0.797

Gnomad ASJ

AF:

0.838

Gnomad EAS

AF:

0.735

Gnomad SAS

AF:

0.853

Gnomad FIN

AF:

0.888

Gnomad MID

AF:

0.899

Gnomad NFE

AF:

0.918

Gnomad OTH

AF:

0.898

GnomAD2 exomes

AF:

0.863

AC:

133341

AN:

154422

AF XY:

0.867

show subpopulations

Gnomad AFR exome

AF:

0.965

Gnomad AMR exome

AF:

0.736

Gnomad ASJ exome

AF:

0.844

Gnomad EAS exome

AF:

0.739

Gnomad FIN exome

AF:

0.886

Gnomad NFE exome

AF:

0.919

Gnomad OTH exome

AF:

0.869

GnomAD4 exome

AF:

0.904

AC:

1265485

AN:

1399272

Hom.:

574049

Cov.:

AF XY:

0.904

AC XY:

623846

AN XY:

690168

show subpopulations

African (AFR)

AF:

0.962

AC:

30410

AN:

31596

American (AMR)

AF:

0.745

AC:

26597

AN:

35694

Ashkenazi Jewish (ASJ)

AF:

0.851

AC:

21416

AN:

25176

East Asian (EAS)

AF:

0.690

AC:

24652

AN:

35726

South Asian (SAS)

AF:

0.876

AC:

69366

AN:

79218

European-Finnish (FIN)

AF:

0.887

AC:

43684

AN:

49252

Middle Eastern (MID)

AF:

0.877

AC:

4995

AN:

5694

European-Non Finnish (NFE)

AF:

0.920

AC:

992227

AN:

1078918

Other (OTH)

AF:

0.899

AC:

52138

AN:

57998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

6171

12342

18512

24683

30854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21112

42224

63336

84448

105560

<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:

0.905

AC:

137834

AN:

152322

Hom.:

62636

Cov.:

AF XY:

0.900

AC XY:

67040

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.960

AC:

39926

AN:

41594

American (AMR)

AF:

0.797

AC:

12196

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.838

AC:

2908

AN:

3470

East Asian (EAS)

AF:

0.735

AC:

3803

AN:

5176

South Asian (SAS)

AF:

0.853

AC:

4111

AN:

4822

European-Finnish (FIN)

AF:

0.888

AC:

9432

AN:

10620

Middle Eastern (MID)

AF:

0.891

AC:

262

AN:

294

European-Non Finnish (NFE)

AF:

0.918

AC:

62440

AN:

68026

Other (OTH)

AF:

0.894

AC:

1890

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

683

1366

2048

2731

3414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

904

1808

2712

3616

4520

<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:

0.902

Hom.:

6643

Bravo

AF:

0.898

Asia WGS

AF:

0.798

AC:

2776

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

Apr 25, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

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

- -

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

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

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

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.049

(source)

DANN

Benign

0.62

PhyloP100

-6.6

Mutation Taster

=100/0

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