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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen
• inherited neurodegenerative disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• myoclonus, intractable, neonatal

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• hereditary spastic paraplegia 10

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004984.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	NM_004984.4	MANE Select	c.*36+5C>T		splice_region intron	N/A	NP_004975.2
	KIF5A	NM_001354705.2		c.*36+5C>T		splice_region intron	N/A	NP_001341634.1	J3KNA1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	ENST00000455537.7	TSL:1 MANE Select	c.*36+5C>T		splice_region intron	N/A	ENSP00000408979.2	Q12840
	KIF5A	ENST00000938849.1		c.*41C>T		3_prime_UTR	Exon 28 of 28	ENSP00000608908.1
	KIF5A	ENST00000676437.1		c.*293C>T		3_prime_UTR	Exon 2 of 2	ENSP00000502358.1	A0A6Q8PGP8

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 10 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs775249;

hg19: chr12-57977003;

COSMIC: COSV54052723;

COSMIC: COSV54052723;