Genetic Variant KIF1A:p.Ala1083Thr (chr2-240745865-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001379631.1(KIF1A):c.3322G>A(p.Ala1108Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,611,754 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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. A1108L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 2 hom. )

Consequence

KIF1A
NM_001379631.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: -0.776

Publications

3 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056268275).

BP6

Variant 2-240745865-C-T is Benign according to our data. Variant chr2-240745865-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 335271.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000197 (30/152296) while in subpopulation EAS AF = 0.00406 (21/5170). AF 95% confidence interval is 0.00272. There are 1 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379631.1. 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.3247G>A	p.Ala1083Thr	missense	Exon 31 of 49	NP_001230937.1
KIF1A	NM_001379631.1		c.3322G>A	p.Ala1108Thr	missense	Exon 31 of 49	NP_001366560.1
KIF1A	NM_001379642.1		c.3220G>A	p.Ala1074Thr	missense	Exon 30 of 49	NP_001366571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3247G>A	p.Ala1083Thr	missense	Exon 31 of 49	ENSP00000438388.1
KIF1A	ENST00000675932.2		c.3247G>A	p.Ala1083Thr	missense	Exon 31 of 49	ENSP00000502786.2
KIF1A	ENST00000675314.2		c.3376G>A	p.Ala1126Thr	missense	Exon 32 of 50	ENSP00000502584.2

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00405

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000279

AC:

AN:

243856

AF XY:

0.000301

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00274

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000155

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000289

AC:

422

AN:

1459458

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

207

AN XY:

725790

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33444

American (AMR)

AF:

0.0000225

AC:

AN:

44510

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26022

East Asian (EAS)

AF:

0.00676

AC:

268

AN:

39662

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1111020

Other (OTH)

AF:

0.000133

AC:

AN:

60306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

102

128

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:

0.000197

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00406

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000194

Hom.:

Bravo

AF:

0.000159

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000356

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000179

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 30 (1)

Inborn genetic diseases (1)

KIF1A-related disorder (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

4.1

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.099

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.81

M_CAP

Benign

0.027

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.26

PhyloP100

-0.78

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.42

REVEL

Benign

0.060

Sift

Benign

0.50

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.069

MVP

0.42

MPC

0.42

ClinPred

0.0069

GERP RS

1.3

PromoterAI

0.016

Neutral

(source)

Varity_R

0.028

gMVP

0.50

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over