2-240785066-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001244008.2(KIF1A):c.643A>C(p.Ser215Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S215N) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.73

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr2-240785065-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 989192.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 2-240785066-T-G is Pathogenic according to our data. Variant chr2-240785066-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 162057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.643A>C	p.Ser215Arg	missense_variant	Exon 7 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.643A>C	p.Ser215Arg	missense_variant	Exon 7 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 9

Pathogenic:3

Mar 31, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 29, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 01, 2014

CHU Sainte-Justine Research Center, University of Montreal

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 30

Pathogenic:1

Sep 21, 2023

Genomic Medicine Lab, University of California San Francisco

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Sep 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

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

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.1

H;H;.;.;.;.;.;H;.;.;.;H;.

PhyloP100

7.7

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.2

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.98, 0.97

MutPred

0.91

Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);

MVP

0.94

MPC

2.5

ClinPred

1.0

GERP RS

4.1

Varity_R

0.95

gMVP

1.0

Mutation Taster

=5/95

disease causing (ClinVar)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over