rs112333674

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.1444-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,559,788 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 111 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 109 hom. )

Consequence

KIF7
NM_198525.3 splice_region, intron

Scores

Splicing: ADA: 0.00003085

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -4.11

Publications

2 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 (BayesDel_noAF=-0.87).

BP6

Variant 15-89647716-T-C is Benign according to our data. Variant chr15-89647716-T-C is described in ClinVar as Benign. ClinVar VariationId is 129405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.1444-4A>G		splice_region_variant, intron_variant	Intron 5 of 18	ENST00000394412.8	NP_940927.2	Q2M1P5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF7	ENST00000394412.8 link	c.1444-4A>G		splice_region_variant, intron_variant	Intron 5 of 18	5	NM_198525.3	ENSP00000377934.3		Q2M1P5
KIF7	ENST00000696512.1 link	c.1567-4A>G		splice_region_variant, intron_variant	Intron 5 of 18			ENSP00000512678.1		A0A8Q3SIQ8

Frequencies

GnomAD3 genomes

AF:

0.0203

AC:

3081

AN:

152052

Hom.:

110

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0705

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00512

AC:

865

AN:

168812

AF XY:

0.00380

show subpopulations

Gnomad AFR exome

AF:

0.0785

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.00172

GnomAD4 exome

AF:

0.00217

AC:

3060

AN:

1407618

Hom.:

109

Cov.:

AF XY:

0.00183

AC XY:

1278

AN XY:

696478

show subpopulations

African (AFR)

AF:

0.0772

AC:

2487

AN:

32210

American (AMR)

AF:

0.00313

AC:

119

AN:

37960

Ashkenazi Jewish (ASJ)

AF:

0.0000394

AC:

AN:

25358

East Asian (EAS)

AF:

0.00

AC:

AN:

37022

South Asian (SAS)

AF:

0.000223

AC:

AN:

80690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43368

Middle Eastern (MID)

AF:

0.00508

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.000121

AC:

131

AN:

1086738

Other (OTH)

AF:

0.00470

AC:

275

AN:

58558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

164

327

491

654

818

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0203

AC:

3086

AN:

152170

Hom.:

111

Cov.:

AF XY:

0.0191

AC XY:

1422

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0704

AC:

2922

AN:

41506

American (AMR)

AF:

0.00712

AC:

109

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

67994

Other (OTH)

AF:

0.0138

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

146

291

437

582

728

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0158

Hom.:

Bravo

AF:

0.0233

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 03, 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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acrocallosal syndrome

Benign:2

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.061

(source)

DANN

Benign

0.60

PhyloP100

-4.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000031

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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