Genetic Variant KIF1A:p.Ser1035Trp (chr2-240746137-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001244008.2(KIF1A):c.3104C>G(p.Ser1035Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000353 in 1,417,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1035L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.72

Publications

0 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, 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

KIF1A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.3104C>G	p.Ser1035Trp	missense_variant	Exon 30 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.3104C>G	p.Ser1035Trp	missense_variant	Exon 30 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000353

AC:

AN:

1417622

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

701192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32426

American (AMR)

AF:

0.00

AC:

AN:

38046

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25372

East Asian (EAS)

AF:

0.00

AC:

AN:

37110

South Asian (SAS)

AF:

0.00

AC:

AN:

80512

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000459

AC:

AN:

1090070

Other (OTH)

AF:

0.00

AC:

AN:

58768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.0

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

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.74

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.4

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

PhyloP100

6.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.0

ClinPred

0.99

GERP RS

4.6

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.58

gMVP

0.77

Mutation Taster

=66/34

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over