rs775249

Positions:

• chr12-57583220-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004984.4(KIF5A):​c.*36+5C>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,559,036 control chromosomes in the GnomAD database, including 57,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (4816 hom., cov: 31)
  • Exomes 𝑓: 0.27 (52222 hom.)
• Consequence: KIF5A NM_004984.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.004336
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.382

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 12-57583220-C-T is Benign according to our data. Variant chr12-57583220-C-T is described in ClinVar as [Benign]. Clinvar id is 309953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57583220-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.274 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4	c.*36+5C>T		splice_donor_5th_base_variant, intron_variant		ENST00000455537.7
KIF5A	NM_001354705.2	c.*36+5C>T		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.*36+5C>T		splice_donor_5th_base_variant, intron_variant		1	NM_004984.4	P1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37762 AN: 151870 Hom.: 4808 Cov.: 31

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.251 AC: 58030 AN: 231228 Hom.: 7415 AF XY: 0.252 AC XY: 31503 AN XY: 125054

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.197

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.270 AC: 380595 AN: 1407046 Hom.: 52222 Cov.: 23 AF XY: 0.268 AC XY: 187857 AN XY: 701868

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.245

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.331

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.249 AC: 37792 AN: 151990 Hom.: 4816 Cov.: 31 AF XY: 0.251 AC XY: 18633 AN XY: 74278

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.332

Gnomad4 NFE AF: 0.277

Gnomad4 OTH AF: 0.257

Alfa AF: 0.256 Hom.: 1445

Bravo AF: 0.240

Asia WGS AF: 0.183 AC: 639 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 22, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Hereditary spastic paraplegia 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jan 20, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0043
dbscSNV1_RF	Benign	0.10
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

LitVar

Other links and lift over

dbSNP: rs775249; hg19: chr12-57977003; COSMIC: COSV54052723; COSMIC: COSV54052723;