rs672601367

Positions:

• chr2-240785066-T-G

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.643A>C​(p.Ser215Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S215N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.73

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr2-240785065-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 989192.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.987
• PP5: Variant 2-240785066-T-G is Pathogenic according to our data. Variant chr2-240785066-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 162057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.643A>C	p.Ser215Arg	missense_variant	7/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.643A>C	p.Ser215Arg	missense_variant	7/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 9 Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	CHU Sainte-Justine Research Center, University of Montreal	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Mar 31, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 29, 2014	- -

Hereditary spastic paraplegia 30 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Sep 21, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H;.;.;.;.;.;H;.;.;.;H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.2	.;D;D;.;.;.;.;.;.;.;.;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.;.;D;.;.;.;D;.
Vest4		0.98, 0.97
MutPred		0.91		Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);
MVP		0.94
MPC		2.5
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		1.0

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: rs672601367; hg19: chr2-241724483;