Genetic Variant KIF1A:p.Gly117Asp (chr2-240788064-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_001244008.2(KIF1A):c.350G>A(p.Gly117Asp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G117S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.70

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal dominant 9
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
syndromic intellectual disability
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neuropathy, hereditary sensory, type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary spastic paraplegia 30
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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

KIF1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240788064-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 520815.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 2-240788064-C-T is Pathogenic according to our data. Variant chr2-240788064-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 936699.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1A	NM_001244008.2	MANE Select	c.350G>A	p.Gly117Asp	missense	Exon 4 of 49	NP_001230937.1	Q12756-3
KIF1A	NM_001379631.1		c.350G>A	p.Gly117Asp	missense	Exon 4 of 49	NP_001366560.1
KIF1A	NM_001379642.1		c.350G>A	p.Gly117Asp	missense	Exon 4 of 49	NP_001366571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.350G>A	p.Gly117Asp	missense	Exon 4 of 49	ENSP00000438388.1	Q12756-3
KIF1A	ENST00000675932.2		c.350G>A	p.Gly117Asp	missense	Exon 4 of 49	ENSP00000502786.2	A0A6Q8PHQ5
KIF1A	ENST00000675314.2		c.479G>A	p.Gly160Asp	missense	Exon 5 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

189308

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1175822

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

584028

African (AFR)

AF:

0.00

AC:

AN:

26148

American (AMR)

AF:

0.00

AC:

AN:

34350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19294

East Asian (EAS)

AF:

0.00

AC:

AN:

23236

South Asian (SAS)

AF:

0.00

AC:

AN:

77366

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35708

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4804

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

908800

Other (OTH)

AF:

0.00

AC:

AN:

46116

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

PhyloP100

7.7

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.93

Gain of disorder (P = 0.127)

MVP

0.95

MPC

2.7

ClinPred

1.0

GERP RS

4.8

Varity_R

0.95

gMVP

1.0

Mutation Taster

=7/93

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over