rs387906798

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_001244008.2(KIF1A):c.764C>T(p.Ala255Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A255D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.69

Publications

14 publications found

Variant links:

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 9
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuropathy, hereditary sensory, type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
hereditary spastic paraplegia 30
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
PEHO syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary sensory and autonomic neuropathy type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001244008.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240783773-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2035801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.905

PP5

Variant 2-240783773-G-A is Pathogenic according to our data. Variant chr2-240783773-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30166.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.764C>T	p.Ala255Val	missense_variant	Exon 8 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.764C>T	p.Ala255Val	missense_variant	Exon 8 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1434384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710804

African (AFR)

AF:

0.00

AC:

AN:

32912

American (AMR)

AF:

0.00

AC:

AN:

41550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25576

East Asian (EAS)

AF:

0.00

AC:

AN:

38332

South Asian (SAS)

AF:

0.00

AC:

AN:

81822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098794

Other (OTH)

AF:

0.00

AC:

AN:

59346

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spastic paraplegia 30b, autosomal recessive

Pathogenic:1

Jun 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;.;.;.;.;.;D;.;.;.;.;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

0.81

L;L;.;.;.;.;.;L;.;.;.;L;.

PhyloP100

9.7

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.3

.;D;D;.;.;.;.;.;.;.;.;D;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

.;D;D;.;.;.;.;.;.;.;.;D;.

Sift4G

Pathogenic

0.0010

.;D;D;.;.;.;.;.;.;.;.;.;.

Polyphen

0.94

P;.;.;.;.;.;.;P;.;.;.;P;.

Vest4

0.94, 0.91

MutPred

0.66

Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);

MVP

0.97

MPC

1.9

ClinPred

0.99

GERP RS

3.4

Varity_R

0.51

gMVP

0.96

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.020

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over