12-57549925-A-G

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

2

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

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
KIF5ANM_004984.4 linkc.-347A>G upstream_gene_variant ENST00000455537.7 NP_004975.2 Q12840
KIF5ANM_001354705.2 linkc.-347A>G upstream_gene_variant NP_001341634.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF5AENST00000455537.7 linkc.-347A>G upstream_gene_variant 1 NM_004984.4 ENSP00000408979.2 Q12840

Frequencies

GnomAD3 genomes
AF:
0.00863
AC:
1309
AN:
151698
Hom.:
21
Cov.:
31
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:
45
AN:
151220
Hom.:
0
AF XY:
0.000230
AC XY:
19
AN XY:
82524
show subpopulations
African (AFR)
AF:
0.0213
AC:
30
AN:
1408
American (AMR)
AF:
0.00129
AC:
6
AN:
4658
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3308
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3922
South Asian (SAS)
AF:
0.000104
AC:
3
AN:
28912
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9064
Middle Eastern (MID)
AF:
0.00182
AC:
1
AN:
550
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
91572
Other (OTH)
AF:
0.000639
AC:
5
AN:
7826
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.514
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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.:
21
Cov.:
31
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:
46
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5146
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4804
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10582
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000590
AC:
4
AN:
67802
Other (OTH)
AF:
0.00475
AC:
10
AN:
2104
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
65
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
0
20
40
60
80
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.:
0
Bravo
AF:
0.00943
Asia WGS
AF:
0.00202
AC:
7
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
DANN
Benign
0.29
PhyloP100
-0.51
PromoterAI
0.23
Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs115259738; hg19: chr12-57943708; API