rs199624091

chr12-57567626-G-Achr12-57567626-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004984.4(KIF5A):c.714+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,611,082 control chromosomes in the GnomAD database, including 2 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: KIF5A NM_004984.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001816
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.322

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=-0.92).
• BP6: Variant 12-57567626-G-A is Benign according to our data. Variant chr12-57567626-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 219405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57567626-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0014 (212/151288) while in subpopulation AMR AF= 0.00276 (42/15198). AF 95% confidence interval is 0.0021. There are 0 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 212 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4	c.714+8G>A		splice_region_variant, intron_variant		ENST00000455537.7
KIF5A	NM_001354705.2	c.447+8G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.714+8G>A		splice_region_variant, intron_variant		1	NM_004984.4	P1
KIF5A	ENST00000286452.5	c.447+8G>A		splice_region_variant, intron_variant		2
KIF5A	ENST00000674619.1	c.714+8G>A		splice_region_variant, intron_variant
KIF5A	ENST00000676457.1	c.609+8G>A		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 212 AN: 151184 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.000682

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00277

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.00121 AC: 300 AN: 248916 Hom.: 0 AF XY: 0.00109 AC XY: 147 AN XY: 134488

Gnomad AFR exome AF: 0.000559

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000375

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00163 AC: 2373 AN: 1459794 Hom.: 2 Cov.: 34 AF XY: 0.00151 AC XY: 1097 AN XY: 726168

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00244

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000339

Gnomad4 NFE exome AF: 0.00191

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00140 AC: 212 AN: 151288 Hom.: 0 Cov.: 27 AF XY: 0.00149 AC XY: 110 AN XY: 73894

Gnomad4 AFR AF: 0.000680

Gnomad4 AMR AF: 0.00276

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000480

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000949 Hom.: 0

Bravo AF: 0.00145

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KIF5A: BP4, BS1 -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	5.7
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
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: rs199624091; hg19: chr12-57961409;