Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS1

The NM_001244008.2(KIF1A):c.4374C>T(p.Gly1458Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,551,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -3.68

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.021).

BP6

Variant 2-240723503-G-A is Benign according to our data. Variant chr2-240723503-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464249.

BP7

Synonymous conserved (PhyloP=-3.68 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000843 (118/1399630) while in subpopulation AMR AF = 0.00266 (96/36096). AF 95% confidence interval is 0.00223. There are 0 homozygotes in GnomAdExome4. There are 55 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

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.4374C>T	p.Gly1458Gly	synonymous	Exon 42 of 49	NP_001230937.1
KIF1A	NM_001379631.1		c.4449C>T	p.Gly1483Gly	synonymous	Exon 42 of 49	NP_001366560.1
KIF1A	NM_001379642.1		c.4374C>T	p.Gly1458Gly	synonymous	Exon 42 of 49	NP_001366571.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.4374C>T	p.Gly1458Gly	synonymous	Exon 42 of 49	ENSP00000438388.1
KIF1A	ENST00000460788.5	TSL:1	n.931C>T		non_coding_transcript_exon	Exon 2 of 9
KIF1A	ENST00000492812.6	TSL:1	n.2957C>T		non_coding_transcript_exon	Exon 9 of 16

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000574

AC:

AN:

158622

AF XY:

0.000522

show subpopulations

Gnomad AFR exome

AF:

0.000121

Gnomad AMR exome

AF:

0.00347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000177

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000160

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000843

AC:

118

AN:

1399630

Hom.:

Cov.:

AF XY:

0.0000797

AC XY:

AN XY:

690510

show subpopulations

African (AFR)

AF:

0.0000947

AC:

AN:

31692

American (AMR)

AF:

0.00266

AC:

AN:

36096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25214

East Asian (EAS)

AF:

0.0000556

AC:

AN:

35992

South Asian (SAS)

AF:

0.00

AC:

AN:

79266

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48128

Middle Eastern (MID)

AF:

0.000202

AC:

AN:

4942

European-Non Finnish (NFE)

AF:

0.00000926

AC:

AN:

1080258

Other (OTH)

AF:

0.000103

AC:

AN:

58042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.0000854

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41448

American (AMR)

AF:

0.000458

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

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:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000113

Hom.:

Bravo

AF:

0.000317

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)

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

BayesDel_noAF

Benign

-0.63

CADD

Benign

2.1

(source)

DANN

Benign

0.90

PhyloP100

-3.7

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over