rs769965899

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001244008.2(KIF1A):c.4555G>A(p.Glu1519Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000772 in 1,554,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. E1519D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.02

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, 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07286245).

BP6

Variant 2-240722566-C-T is Benign according to our data. Variant chr2-240722566-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447654.

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
KIF1A	NM_001244008.2	MANE Select	c.4555G>A	p.Glu1519Lys	missense	Exon 43 of 49	NP_001230937.1
KIF1A	NM_001379631.1		c.4630G>A	p.Glu1544Lys	missense	Exon 43 of 49	NP_001366560.1
KIF1A	NM_001379642.1		c.4555G>A	p.Glu1519Lys	missense	Exon 43 of 49	NP_001366571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.4555G>A	p.Glu1519Lys	missense	Exon 43 of 49	ENSP00000438388.1
KIF1A	ENST00000460788.5	TSL:1	n.1112G>A		non_coding_transcript_exon	Exon 3 of 9
KIF1A	ENST00000492812.6	TSL:1	n.3138G>A		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

161172

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

AF:

0.00000784

AC:

AN:

1402438

Hom.:

Cov.:

AF XY:

0.00000578

AC XY:

AN XY:

692212

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31958

American (AMR)

AF:

0.00

AC:

AN:

36792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.00

AC:

AN:

36448

South Asian (SAS)

AF:

0.00

AC:

AN:

79446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4872

European-Non Finnish (NFE)

AF:

0.00000832

AC:

AN:

1081490

Other (OTH)

AF:

0.0000172

AC:

AN:

58078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000882

AC:

ClinVar

ClinVar submissions as Germline

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 specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.067

MetaRNN

Benign

0.073

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.3

PhyloP100

3.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.91

REVEL

Benign

0.097

Sift

Benign

1.0

Sift4G

Benign

0.91

Polyphen

0.30

Vest4

0.42

MutPred

0.23

Gain of ubiquitination at E1418 (P = 0.0077)

MVP

0.69

MPC

0.53

ClinPred

0.42

GERP RS

3.6

Varity_R

0.14

gMVP

0.61

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over