rs672601365

chr2-240786444-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001244008.2(KIF1A):c.499C>T(p.Arg167Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167H) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.51

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr2-240786443-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 974913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KIF1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 2-240786444-G-A is Pathogenic according to our data. Variant chr2-240786444-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240786444-G-A is described in Lovd as [Pathogenic]. Variant chr2-240786444-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.499C>T	p.Arg167Cys	missense_variant	6/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.499C>T	p.Arg167Cys	missense_variant	6/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	CHU Sainte-Justine Research Center, University of Montreal	Jan 01, 2014	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 15, 2020	This variant is interpreted as likely pathogenic for NESCAV syndrome, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Assumed de novo, but no confirmation of paternity and maternity (PM6); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PP2). -

Hereditary spastic paraplegia 30 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Paris Brain Institute, Inserm - ICM

-

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 28, 2022

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIF1A protein function. ClinVar contains an entry for this variant (Variation ID: 162055). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 25265257, 26410750). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 167 of the KIF1A protein (p.Arg167Cys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4		0.75, 0.76
MutPred		0.71		Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);Loss of disorder (P = 0.018);
MVP		0.89
MPC		2.8
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.65
gMVP		0.95

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

Other links and lift over

dbSNP: rs672601365; hg19: chr2-241725861; COSMIC: COSV57488467; COSMIC: COSV57488467;