rs749718096

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP3_Moderate

The NM_001244008.2(KIF1A):​c.947G>T​(p.Arg316Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R316Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

KIF1A
NM_001244008.2 missense

Scores

8
9
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.98
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-240775862-C-T is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in the KIF1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 112 curated pathogenic missense variants (we use a threshold of 10). The gene has 150 curated benign missense variants. Gene score misZ: 5.1579 (above the threshold of 3.09). Trascript score misZ: 5.0191 (above the threshold of 3.09). GenCC associations: The gene is linked to neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.947G>T p.Arg316Leu missense_variant Exon 11 of 49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkc.947G>T p.Arg316Leu missense_variant Exon 11 of 49 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.0000165
AC:
2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.84
D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.82
.;T;T;T;T;T;.;T;T;T;T;T;T;T
M_CAP
Pathogenic
0.71
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Uncertain
2.6
M;M;.;.;.;.;.;M;.;.;.;.;M;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-6.1
.;D;D;.;.;.;.;.;.;.;.;.;D;.
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0010
.;D;D;.;.;.;.;.;.;.;.;.;D;.
Sift4G
Uncertain
0.0030
.;D;D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;D;.;.;.;.;D;.
Vest4
0.83, 0.86
MutPred
0.73
Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);.;Loss of catalytic residue at R316 (P = 0.0685);Loss of catalytic residue at R316 (P = 0.0685);
MVP
0.78
MPC
2.6
ClinPred
1.0
D
GERP RS
4.3
Varity_R
0.91
gMVP
0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs749718096; hg19: chr2-241715279; COSMIC: COSV100239902; COSMIC: COSV100239902; API