15-89649809-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_198525.3(KIF7):c.461G>A(p.Arg154Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000909 in 1,551,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 3.24

Publications

1 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: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12053889).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000492 (75/152350) while in subpopulation AFR AF = 0.00178 (74/41590). AF 95% confidence interval is 0.00145. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.461G>A	p.Arg154Gln	missense_variant	Exon 3 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.461G>A	p.Arg154Gln	missense_variant	Exon 3 of 19	5	NM_198525.3	ENSP00000377934.3	Q2M1P5
KIF7	ENST00000445906.1 link	n.*120G>A		non_coding_transcript_exon_variant	Exon 3 of 5	1		ENSP00000395906.1	F8WD21
KIF7	ENST00000445906.1 link	n.*120G>A		3_prime_UTR_variant	Exon 3 of 5	1		ENSP00000395906.1	F8WD21
KIF7	ENST00000696512.1 link	c.584G>A	p.Arg195Gln	missense_variant	Exon 3 of 19			ENSP00000512678.1	A0A8Q3SIQ8

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000108

AC:

AN:

156920

AF XY:

0.0000602

show subpopulations

Gnomad AFR exome

AF:

0.00151

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000329

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1399442

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

690230

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

31598

American (AMR)

AF:

0.000112

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49296

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00000556

AC:

AN:

1078982

Other (OTH)

AF:

0.000103

AC:

AN:

58012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000492

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41590

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000263

Hom.:

Bravo

AF:

0.000570

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Jun 06, 2023

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

Sep 15, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported previously in the heterozygous state with a second KIF7 variant in an individual with features of acrocallosal syndrome (Tunovic et al., 2015).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26633542, 25131622, 26174511) -

Jun 21, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The KIF7 p.Arg154Gln variant was identified in two individuals with neurodevelopmental features similar to acrocallosal syndrome (Tunovic_2015_PMID:26174511; Srivastava_2014_PMID:25131622). These individuals were compound heterozygous for the KIF7 p.Arg154Gln variant and either p.Glu987Lys or p.E987K. The variant was identified in dbSNP (ID: rs180758272) and ClinVar (classified as uncertain significance by Invitae and EGL Genetic Diagnostics). The variant was identified in control databases in 31 of 188318 chromosomes at a frequency of 0.0001646 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 26 of 16664 chromosomes (freq: 0.00156), Latino in 3 of 25532 chromosomes (freq: 0.000118) and European (non-Finnish) in 2 of 76266 chromosomes (freq: 0.000026), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Arg154 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

KIF7-related disorder

Uncertain:1

Sep 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The KIF7 c.461G>A variant is predicted to result in the amino acid substitution p.Arg154Gln. This variant has been reported in the literature in patients with the KIF7-related disease (for example, see Srivastava et al. 2014. PubMed ID: 25131622) This variant is reported in 0.16% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Jan 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

KIF7-related ciliopathy spectrum disorder

Uncertain:1

Oct 29, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The KIF7 c.461G>A (p.Arg154Gln) missense variant has been reported in one study in which it is identified in a heterozygous state of unknown inheritance in one individual with KIF7-related ciliopathy spectrum disorder. The affected individual also carried a second missense variant in the KIF7 gene in a heterozygous state, which was shown to be maternally inherited. Paternal DNA was not available for testing (Tunovic et al. 2015). The p.Arg154Gln variant is reported at a frequency of 0.001560 in the African population of the Genome Aggregation Database in a region of good sequence coverage. The Arg154 residue is located in the kinesin motor domain. Based on the limited evidence, the p.Arg154Gln variant is classified as a variant of unknown significance for KIF7-related ciliopathy spectrum disorder. -

Acrocallosal syndrome

Uncertain:1

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 154 of the KIF7 protein (p.Arg154Gln). This variant is present in population databases (rs180758272, gnomAD 0.2%). This missense change has been observed in individual(s) with acrocallosal syndrome (PMID: 26174511). ClinVar contains an entry for this variant (Variation ID: 463144). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.084

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.0

PhyloP100

3.2

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.29

Sift

Uncertain

0.022

Sift4G

Benign

0.24

Polyphen

0.41

Vest4

0.72

MVP

0.59

MPC

0.040

ClinPred

0.034

GERP RS

3.1

Varity_R

0.39

gMVP

0.52

Mutation Taster

=74/26

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