dbSNP rs774256831: KIF1A:p.Val1673Phe (chr2-240719778-C-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_001244008.2(KIF1A):c.5017G>T(p.Val1673Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V1673A) has been classified as Likely benign.

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

Not reported in ClinVar

Conservation

PhyloP100: 7.42

Publications

0 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: 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
KIF1A	NM_001244008.2 link	c.5017G>T	p.Val1673Phe	missense_variant	Exon 46 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.5017G>T	p.Val1673Phe	missense_variant	Exon 46 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:

1428984

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707634

African (AFR)

AF:

0.00

AC:

AN:

32404

American (AMR)

AF:

0.00

AC:

AN:

41922

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24110

East Asian (EAS)

AF:

0.00

AC:

AN:

38602

South Asian (SAS)

AF:

0.00

AC:

AN:

81050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1094970

Other (OTH)

AF:

0.00

AC:

AN:

59054

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

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

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.48

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.;.;M;.;.;.;.;.;.

PhyloP100

7.4

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.5

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

REVEL

Benign

0.15

Sift

Benign

0.092

.;T;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.21

.;T;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.95

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

Vest4

0.70

MutPred

0.37

Loss of sheet (P = 0.0817);.;.;.;.;.;.;Loss of sheet (P = 0.0817);.;.;.;.;.;.;

MVP

0.14

MPC

1.4

ClinPred

0.99

GERP RS

4.1

Varity_R

0.48

gMVP

0.45

Mutation Taster

=36/64

disease causing

(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