rs201825284

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001244008.2(KIF1A):c.4781C>T(p.Ser1594Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,610,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1594S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00015 ( 1 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 7.45

Publications

4 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=0.07873595).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000473 (72/152330) while in subpopulation AMR AF = 0.00294 (45/15310). AF 95% confidence interval is 0.00226. There are 1 homozygotes in GnomAd4. There are 43 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.4781C>T	p.Ser1594Leu	missense_variant	Exon 45 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.4781C>T	p.Ser1594Leu	missense_variant	Exon 45 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000255

AC:

AN:

242990

AF XY:

0.000241

show subpopulations

Gnomad AFR exome

AF:

0.000336

Gnomad AMR exome

AF:

0.000674

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000338

Gnomad FIN exome

AF:

0.000146

Gnomad NFE exome

AF:

0.0000910

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000145

AC:

212

AN:

1458646

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

725396

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33468

American (AMR)

AF:

0.000539

AC:

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.0000767

AC:

AN:

26078

East Asian (EAS)

AF:

0.000252

AC:

AN:

39654

South Asian (SAS)

AF:

0.000268

AC:

AN:

85664

European-Finnish (FIN)

AF:

0.000134

AC:

AN:

52124

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.000112

AC:

125

AN:

1111138

Other (OTH)

AF:

0.0000830

AC:

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.000473

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41576

American (AMR)

AF:

0.00294

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000180

Hom.:

Bravo

AF:

0.000404

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000504

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000258

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jan 22, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a patient in the published literature with caudal regression syndrome who had another KIF1A variant on the opposite allele (in trans); however, the patient also had variants in two other genes that may have been responsible for the phenotype (PMID: 28007035); Identified heterozygous in a patient with congenital spastic paraplegia, intellectual disability, epilepsy, microcephaly, and brain abnormalities in published literature; however, familial segregation information was not available (PMID: 32737135); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(S1594L); This variant is associated with the following publications: (PMID: 28007035, 32737135) -

Jul 18, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2 -

not specified

Uncertain:1

Jul 29, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Oct 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4478C>T (p.S1493L) alteration is located in exon 43 (coding exon 42) of the KIF1A gene. This alteration results from a C to T substitution at nucleotide position 4478, causing the serine (S) at amino acid position 1493 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia

Uncertain:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

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

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.079

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

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.3

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

PhyloP100

7.5

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.6

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

REVEL

Uncertain

0.30

Sift

Uncertain

0.024

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

Sift4G

Benign

0.090

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

Polyphen

0.17

B;.;.;.;.;.;.;B;.;.;.;.;.;.

Vest4

0.49

MVP

0.60

MPC

0.74

ClinPred

0.13

GERP RS

4.0

PromoterAI

-0.0085

Neutral

(source)

Varity_R

0.12

gMVP

0.38

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over