Genetic Variant NM_198525.3:c.2735A>T (chr15-89632980-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_198525.3(KIF7):c.2735A>T(p.Lys912Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000074 in 1,351,680 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K912R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

KIF7
NM_198525.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.18

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF7	NM_198525.3 link	c.2735A>T	p.Lys912Met	missense_variant	Exon 14 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.2735A>T	p.Lys912Met	missense_variant	Exon 14 of 19	5	NM_198525.3	ENSP00000377934.3	Q2M1P5
KIF7	ENST00000696512.1 link	c.2858A>T	p.Lys953Met	missense_variant	Exon 14 of 19			ENSP00000512678.1	A0A8Q3SIQ8
KIF7	ENST00000677187.1 link	n.409A>T		non_coding_transcript_exon_variant	Exon 2 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.40e-7

AC:

AN:

1351680

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672428

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30218

American (AMR)

AF:

0.00

AC:

AN:

42556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22718

East Asian (EAS)

AF:

0.00

AC:

AN:

35792

South Asian (SAS)

AF:

0.00

AC:

AN:

85160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5374

European-Non Finnish (NFE)

AF:

9.65e-7

AC:

AN:

1036436

Other (OTH)

AF:

0.00

AC:

AN:

54018

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.57

MutationAssessor

Uncertain

2.3

PhyloP100

6.2

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.27

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.58

MutPred

0.29

Loss of ubiquitination at K912 (P = 0.0051);

MVP

0.58

MPC

0.16

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.53

Mutation Taster

=51/49

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over