Genetic Variant KIF7:p.Arg387Gly (chr15-89648539-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_198525.3(KIF7):c.1159C>G(p.Arg387Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000179 in 1,119,716 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R387S) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.65

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35779005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.1159C>G	p.Arg387Gly	missense_variant	Exon 5 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.1159C>G	p.Arg387Gly	missense_variant	Exon 5 of 19	5	NM_198525.3	ENSP00000377934.3	Q2M1P5
KIF7	ENST00000445906.1 link	n.*818C>G		non_coding_transcript_exon_variant	Exon 5 of 5	1		ENSP00000395906.1	F8WD21
KIF7	ENST00000445906.1 link	n.*818C>G		3_prime_UTR_variant	Exon 5 of 5	1		ENSP00000395906.1	F8WD21
KIF7	ENST00000696512.1 link	c.1282C>G	p.Arg428Gly	missense_variant	Exon 5 of 19			ENSP00000512678.1	A0A8Q3SIQ8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000179

AC:

AN:

1119716

Hom.:

Cov.:

AF XY:

0.00000367

AC XY:

AN XY:

544350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20362

American (AMR)

AF:

0.00

AC:

AN:

9666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13886

East Asian (EAS)

AF:

0.00

AC:

AN:

20284

South Asian (SAS)

AF:

0.0000207

AC:

AN:

48298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3332

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

934940

Other (OTH)

AF:

0.00

AC:

AN:

42936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.0084

BayesDel_noAF

Benign

-0.25

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.0016

Eigen_PC

Benign

0.049

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.60

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.36

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.90

PhyloP100

3.7

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-2.1

REVEL

Benign

0.15

Sift

Benign

0.14

Sift4G

Benign

0.31

Polyphen

0.56

Vest4

0.35

MutPred

0.17

Gain of methylation at R389 (P = 0.1038);

MVP

0.75

MPC

0.16

ClinPred

0.75

GERP RS

3.5

Varity_R

0.31

gMVP

0.55

Mutation Taster

=73/27

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over