rs553968087

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_198525.3(KIF7):c.1177G>T(p.Gly393Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,132,710 control chromosomes in the GnomAD database, including 9 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00042 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 6 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4O:1

Conservation

PhyloP100: 2.02

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003365159).

BP6

Variant 15-89648521-C-A is Benign according to our data. Variant chr15-89648521-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283923.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000422 (62/146944) while in subpopulation SAS AF = 0.0104 (50/4816). AF 95% confidence interval is 0.00809. There are 3 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.1177G>T	p.Gly393Cys	missense_variant	Exon 5 of 19	ENST00000394412.8	NP_940927.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KIF7	ENST00000394412.8 link	c.1177G>T	p.Gly393Cys	missense_variant	Exon 5 of 19	5	NM_198525.3	ENSP00000377934.3
KIF7	ENST00000445906.1 link	n.*836G>T		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000395906.1
KIF7	ENST00000445906.1 link	n.*836G>T		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000395906.1
KIF7	ENST00000696512.1 link	c.1300G>T	p.Gly434Cys	missense_variant	Exon 5 of 19			ENSP00000512678.1

Frequencies

GnomAD3 genomes

AF:

0.000409

AC:

AN:

146856

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00995

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000106

Gnomad OTH

AF:

0.000986

GnomAD2 exomes

AF:

0.00211

AC:

AN:

2370

AF XY:

0.00324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000338

AC:

333

AN:

985766

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

224

AN XY:

469190

show subpopulations

African (AFR)

AF:

0.0000554

AC:

AN:

18058

American (AMR)

AF:

0.000227

AC:

AN:

4404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8950

East Asian (EAS)

AF:

0.00

AC:

AN:

13626

South Asian (SAS)

AF:

0.00876

AC:

257

AN:

29328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

17600

Middle Eastern (MID)

AF:

0.00460

AC:

AN:

2390

European-Non Finnish (NFE)

AF:

0.0000456

AC:

AN:

855842

Other (OTH)

AF:

0.000675

AC:

AN:

35568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000422

AC:

AN:

146944

Hom.:

Cov.:

AF XY:

0.000601

AC XY:

AN XY:

71558

show subpopulations

African (AFR)

AF:

0.0000487

AC:

AN:

41038

American (AMR)

AF:

0.00

AC:

AN:

14794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.000196

AC:

AN:

5102

South Asian (SAS)

AF:

0.0104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8486

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000106

AC:

AN:

66058

Other (OTH)

AF:

0.000978

AC:

AN:

2046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.00228

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Feb 27, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIF7: BS2 -

Acrocallosal syndrome

Uncertain:1Benign:1

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 393 of the KIF7 protein (p.Gly393Cys). 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 variant has not been reported in the literature in individuals affected with KIF7-related conditions. ClinVar contains an entry for this variant (Variation ID: 283923). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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. -

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. -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Dec 16, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Acrocallosal syndrome;C2931104:Hydrolethalus syndrome

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 02-25-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.24

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.20

PhyloP100

2.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-2.3

REVEL

Benign

0.17

Sift

Benign

0.13

Sift4G

Benign

0.066

Polyphen

0.0

Vest4

0.16

MutPred

0.27

Gain of helix (P = 0.0128);

MVP

0.35

MPC

0.018

ClinPred

0.032

GERP RS

1.5

Varity_R

0.11

gMVP

0.38

Mutation Taster

=94/6

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