2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCCTCCTCC

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_001244008.2(KIF1A):c.2751_2753delGGA(p.Glu917del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,443,684 control chromosomes in the GnomAD database, including 157,487 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 28069 hom., cov: 0)

Exomes 𝑓: 0.51 ( 129418 hom. )

Consequence

KIF1A
NM_001244008.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.22

Publications

17 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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001244008.2

BP6

Variant 2-240757423-ATCC-A is Benign according to our data. Variant chr2-240757423-ATCC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.2751_2753delGGA	p.Glu917del	disruptive_inframe_deletion	Exon 27 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.2751_2753delGGA	p.Glu917del	disruptive_inframe_deletion	Exon 27 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.646

AC:

88747

AN:

137280

Hom.:

28022

Cov.:

show subpopulations

Gnomad AFR

AF:

0.831

Gnomad AMI

AF:

0.649

Gnomad AMR

AF:

0.572

Gnomad ASJ

AF:

0.630

Gnomad EAS

AF:

0.713

Gnomad SAS

AF:

0.458

Gnomad FIN

AF:

0.554

Gnomad MID

AF:

0.634

Gnomad NFE

AF:

0.571

Gnomad OTH

AF:

0.637

GnomAD2 exomes

AF:

0.525

AC:

57824

AN:

110140

AF XY:

0.518

show subpopulations

Gnomad AFR exome

AF:

0.773

Gnomad AMR exome

AF:

0.449

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.646

Gnomad FIN exome

AF:

0.515

Gnomad NFE exome

AF:

0.538

Gnomad OTH exome

AF:

0.546

GnomAD4 exome

AF:

0.508

AC:

663522

AN:

1306324

Hom.:

129418

AF XY:

0.505

AC XY:

324197

AN XY:

642016

show subpopulations

African (AFR)

AF:

0.725

AC:

21238

AN:

29296

American (AMR)

AF:

0.433

AC:

13543

AN:

31290

Ashkenazi Jewish (ASJ)

AF:

0.555

AC:

12891

AN:

23218

East Asian (EAS)

AF:

0.610

AC:

20320

AN:

33332

South Asian (SAS)

AF:

0.418

AC:

28341

AN:

67860

European-Finnish (FIN)

AF:

0.504

AC:

22004

AN:

43676

Middle Eastern (MID)

AF:

0.544

AC:

2848

AN:

5238

European-Non Finnish (NFE)

AF:

0.505

AC:

514083

AN:

1018318

Other (OTH)

AF:

0.522

AC:

28254

AN:

54096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.551

Heterozygous variant carriers

18126

36251

54377

72502

90628

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16338

32676

49014

65352

81690

<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:

0.647

AC:

88841

AN:

137360

Hom.:

28069

Cov.:

AF XY:

0.643

AC XY:

42788

AN XY:

66516

show subpopulations

African (AFR)

AF:

0.832

AC:

31764

AN:

38200

American (AMR)

AF:

0.572

AC:

7645

AN:

13364

Ashkenazi Jewish (ASJ)

AF:

0.630

AC:

2051

AN:

3256

East Asian (EAS)

AF:

0.713

AC:

3310

AN:

4640

South Asian (SAS)

AF:

0.459

AC:

1870

AN:

4070

European-Finnish (FIN)

AF:

0.554

AC:

4941

AN:

8924

Middle Eastern (MID)

AF:

0.629

AC:

171

AN:

272

European-Non Finnish (NFE)

AF:

0.571

AC:

35358

AN:

61926

Other (OTH)

AF:

0.635

AC:

1204

AN:

1896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1484

2968

4452

5936

7420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<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:

0.469

Hom.:

1564

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Aug 26, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Nov 12, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia 30

Benign:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as benign. Following criteria are met: 0308 - Population frequency for this variant is out of keeping with known incidence of spastic paraplegia 30, autosomal recessive (MIM#610357), with 26,739 homozygotes in gnomAD v3. (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

KIF1A related neurological disorder

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

African population allele frequency is 75.16% (rs143816642, 57824/110140 alleles, 11329 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.2

Mutation Taster

=92/8

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over