Genetic Variant KIF5A:c.-25+3613A>G (chr12-57549925-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000676250.1(KIF5A):c.-25+3613A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 303,026 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0086 ( 21 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

KIF5A
ENST00000676250.1 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.508

Publications

1 publications found

Variant links:

Genes affected

KIF5A (HGNC:6323): (kinesin family member 5A) This gene encodes a member of the kinesin family of proteins. Members of this family are part of a multisubunit complex that functions as a microtubule motor in intracellular organelle transport. Mutations in this gene cause autosomal dominant spastic paraplegia 10. [provided by RefSeq, Jul 2008]

KIF5A Gene-Disease associations (from GenCC):

amyotrophic lateral sclerosis, susceptibility to, 25
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina, Labcorp Genetics (formerly Invitae)
inherited neurodegenerative disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
myoclonus, intractable, neonatal
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
hereditary spastic paraplegia 10
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KIF5A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 12-57549925-A-G is Benign according to our data. Variant chr12-57549925-A-G is described in CliVar as Likely_benign. Clinvar id is 1201242.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00865 (1313/151806) while in subpopulation AFR AF = 0.0302 (1253/41422). AF 95% confidence interval is 0.0289. There are 21 homozygotes in GnomAd4. There are 624 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1313 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4 link	c.-347A>G		upstream_gene_variant		ENST00000455537.7	NP_004975.2	Q12840
KIF5A	NM_001354705.2 link	c.-347A>G		upstream_gene_variant			NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7 link	c.-347A>G		upstream_gene_variant		1	NM_004984.4	ENSP00000408979.2		Q12840

Frequencies

GnomAD3 genomes

AF:

0.00863

AC:

1309

AN:

151698

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00302

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:

0.0000590

Gnomad OTH

AF:

0.00480

GnomAD4 exome

AF:

0.000298

AC:

AN:

151220

Hom.:

AF XY:

0.000230

AC XY:

AN XY:

82524

show subpopulations

African (AFR)

AF:

0.0213

AC:

AN:

1408

American (AMR)

AF:

0.00129

AC:

AN:

4658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3308

East Asian (EAS)

AF:

0.00

AC:

AN:

3922

South Asian (SAS)

AF:

0.000104

AC:

AN:

28912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9064

Middle Eastern (MID)

AF:

0.00182

AC:

AN:

550

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

91572

Other (OTH)

AF:

0.000639

AC:

AN:

7826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.00865

AC:

1313

AN:

151806

Hom.:

Cov.:

AF XY:

0.00841

AC XY:

624

AN XY:

74192

show subpopulations

African (AFR)

AF:

0.0302

AC:

1253

AN:

41422

American (AMR)

AF:

0.00301

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5146

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000590

AC:

AN:

67802

Other (OTH)

AF:

0.00475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

130

196

261

326

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00133

Hom.:

Bravo

AF:

0.00943

Asia WGS

AF:

0.00202

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 08, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.3

(source)

DANN

Benign

0.29

PhyloP100

-0.51

PromoterAI

0.23

Neutral

(source)

Splicing

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