rs759791775

chr2-240773155-C-Gchr2-240773155-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3 PP5

The NM_001244008.2(KIF1A):c.1139G>C(p.Arg380Pro) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R380Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.76

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a coiled_coil_region (size 17) in uniprot entity KIF1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr2-240773156-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 583174.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.
• PP2: Missense variant where missense usually causes diseases, KIF1A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant 2-240773155-C-G is Pathogenic according to our data. Variant chr2-240773155-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574511.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.1139G>C	p.Arg380Pro	missense_variant	13/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.1139G>C	p.Arg380Pro	missense_variant	13/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 30 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Mar 02, 2022

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 08, 2018

This sequence change replaces arginine with proline at codon 380 of the KIF1A protein (p.Arg380Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KIF1A-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;.;.;.;.;D;.;.;.;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.7	M;M;.;.;.;.;.;M;.;.;.;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
Polyphen		0.97	D;.;.;.;.;.;.;D;.;.;.;.;D;.
Vest4		0.76, 0.72
MutPred		0.59		Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);.;Gain of glycosylation at T377 (P = 0.1084);Gain of glycosylation at T377 (P = 0.1084);
MVP		0.67
MPC		2.8
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.98

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: rs759791775; hg19: chr2-241712572;