2-240783773-G-T

Variant names:

• chr2-240783773-G-T
• rs387906798
• NM_001244008.2:c.764C>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001244008.2(KIF1A):​c.764C>A​(p.Ala255Asp) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A255V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.69
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30166.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 2-240783773-G-T is Pathogenic according to our data. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.764C>A	p.Ala255Asp	missense	Exon 8 of 49	NP_001230937.1
	KIF1A	NM_001379631.1		c.764C>A	p.Ala255Asp	missense	Exon 8 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.764C>A	p.Ala255Asp	missense	Exon 8 of 49	NP_001366571.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.764C>A	p.Ala255Asp	missense	Exon 8 of 49	ENSP00000438388.1
	KIF1A	ENST00000675932.2		c.764C>A	p.Ala255Asp	missense	Exon 8 of 49	ENSP00000502786.2
	KIF1A	ENST00000675314.2		c.893C>A	p.Ala298Asp	missense	Exon 9 of 50	ENSP00000502584.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1434384 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710804

African (AFR) AF: 0.00 AC: 0 AN: 32912

American (AMR) AF: 0.00 AC: 0 AN: 41550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25576

East Asian (EAS) AF: 0.00 AC: 0 AN: 38332

South Asian (SAS) AF: 0.00 AC: 0 AN: 81822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098794

Other (OTH) AF: 0.00 AC: 0 AN: 59346

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 30 Pathogenic:1

May 22, 2024

Clinical Omics and Informatics (COIN) Unit, Neuroscience Institute, University Of Cape Town

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PM1 met: variant is located in the functional motor domain of the KIF1A protein together with other pathogenic variants. PP3_moderate: REVEL score is 0.88. PP2 met: missense Z-score is 5.158. PP1 not met: variant segregates with 1 informative meiosis in 1 family. PM5 met: KIF1A Ala255Val classified as likely pathogenic (PMID 21487076).

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

Mar 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 255 of the KIF1A protein (p.Ala255Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 2035801). 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 with a positive predictive value of 95%. This variant disrupts the p.A255 amino acid residue in KIF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21487076, 22258533, 25265257, 26125038). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.79		Loss of MoRF binding (P = 0.0729)
MVP		0.93
MPC		2.6
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.94
gMVP		1.0
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs387906798; hg19: chr2-241723190;