rs775249

Variant names:

• chr12-57583220-C-T
• rs775249
• NM_004984.4:c.*36+5C>T

Variant summary

Our verdict is Benign. The variant received -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 region, 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_region, intron
• Scores: Splicing: ADA: 0.004336
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.382
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 309953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
KIF5A	NM_004984.4	c.*36+5C>T		splice_region_variant, intron_variant	Intron 28 of 28	ENST00000455537.7	NP_004975.2
KIF5A	NM_001354705.2	c.*36+5C>T		splice_region_variant, intron_variant	Intron 25 of 25		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7	c.*36+5C>T		splice_region_variant, intron_variant	Intron 28 of 28	1	NM_004984.4	ENSP00000408979.2

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

GnomAD2 exomes AF: 0.251 AC: 58030 AN: 231228 AF XY: 0.252

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 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

African (AFR) AF: 0.197 AC: 6348 AN: 32156

American (AMR) AF: 0.189 AC: 8202 AN: 43420

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 6273 AN: 25596

East Asian (EAS) AF: 0.215 AC: 8351 AN: 38762

South Asian (SAS) AF: 0.197 AC: 16515 AN: 83748

European-Finnish (FIN) AF: 0.331 AC: 17345 AN: 52326

Middle Eastern (MID) AF: 0.238 AC: 1343 AN: 5638

European-Non Finnish (NFE) AF: 0.282 AC: 301137 AN: 1066892

Other (OTH) AF: 0.258 AC: 15081 AN: 58508

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

African (AFR) AF: 0.194 AC: 8038 AN: 41468

American (AMR) AF: 0.230 AC: 3518 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3472

East Asian (EAS) AF: 0.217 AC: 1118 AN: 5154

South Asian (SAS) AF: 0.200 AC: 960 AN: 4810

European-Finnish (FIN) AF: 0.332 AC: 3500 AN: 10540

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18821 AN: 67956

Other (OTH) AF: 0.257 AC: 543 AN: 2112

Alfa AF: 0.254 Hom.: 1565

Bravo AF: 0.240

Asia WGS AF: 0.183 AC: 639 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Dec 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary spastic paraplegia 10 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 20, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		-0.38
PromoterAI		-0.0030	Neutral
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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