NM_198525.3:c.49C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198525.3(KIF7):c.49C>T(p.Arg17Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 1,540,090 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R17Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00051 ( 8 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.09

Publications

6 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=0.011151433).

BP6

Variant 15-89652882-G-A is Benign according to our data. Variant chr15-89652882-G-A is described in ClinVar as Benign. ClinVar VariationId is 129418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00393 (598/152342) while in subpopulation AFR AF = 0.0134 (556/41580). AF 95% confidence interval is 0.0125. There are 3 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198525.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF7	NM_198525.3	MANE Select	c.49C>T	p.Arg17Trp	missense	Exon 2 of 19	NP_940927.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF7	ENST00000394412.8	TSL:5 MANE Select	c.49C>T	p.Arg17Trp	missense	Exon 2 of 19	ENSP00000377934.3
KIF7	ENST00000445906.1	TSL:1	n.49C>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000395906.1
KIF7	ENST00000696512.1		c.172C>T	p.Arg58Trp	missense	Exon 2 of 19	ENSP00000512678.1

Frequencies

GnomAD3 genomes

AF:

0.00392

AC:

597

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00129

AC:

186

AN:

143638

AF XY:

0.00114

show subpopulations

Gnomad AFR exome

AF:

0.0169

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.000486

Gnomad EAS exome

AF:

0.00176

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000370

Gnomad OTH exome

AF:

0.00119

GnomAD4 exome

AF:

0.000509

AC:

707

AN:

1387748

Hom.:

Cov.:

AF XY:

0.000446

AC XY:

305

AN XY:

683134

show subpopulations

African (AFR)

AF:

0.0167

AC:

524

AN:

31450

American (AMR)

AF:

0.00115

AC:

AN:

35548

Ashkenazi Jewish (ASJ)

AF:

0.000360

AC:

AN:

25034

East Asian (EAS)

AF:

0.000562

AC:

AN:

35570

South Asian (SAS)

AF:

0.0000380

AC:

AN:

78890

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44962

Middle Eastern (MID)

AF:

0.000733

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

0.0000391

AC:

AN:

1073354

Other (OTH)

AF:

0.00111

AC:

AN:

57486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

113

151

189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.00393

AC:

598

AN:

152342

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0134

AC:

556

AN:

41580

American (AMR)

AF:

0.00196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68030

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

109

136

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:

0.00142

Hom.:

Bravo

AF:

0.00500

ExAC

AF:

0.00154

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KIF7: BS1, BS2

Apr 13, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

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.

Apr 25, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Acrocallosal syndrome

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Benign

-0.024

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.30

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.36

MutationAssessor

Pathogenic

3.6

PhyloP100

1.1

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.49

MVP

0.62

MPC

0.097

ClinPred

0.060

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.62

gMVP

0.53

Mutation Taster

=86/14

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over