Variant rs191428830 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001244008.2(KIF1A):c.4889G>T(p.Arg1630Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1630Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.76

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]

KIF1A links:

KIF1A (HGNC:):

KIF1A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.27955765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.4889G>T	p.Arg1630Leu	missense_variant	46/49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.4889G>T	p.Arg1630Leu	missense_variant	46/49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

T;.;.;.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.014

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

.;D;D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Benign

0.031

MetaRNN

Benign

0.28

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.;.;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-4.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.083

Sift

Benign

0.058

.;T;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.35

.;T;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.77

P;.;.;.;.;.;.;P;.;.;.;.;.;.

Vest4

0.62

MutPred

0.21

Gain of relative solvent accessibility (P = 0.0166);.;.;.;.;.;.;Gain of relative solvent accessibility (P = 0.0166);.;.;.;.;.;.;

MVP

0.37

MPC

0.84

ClinPred

0.86

GERP RS

4.2

Varity_R

0.17

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over