12-57585407-C-G

Variant names:

• chr12-57585407-C-G
• rs1678536
• NM_004984.4:c.*1226C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004984.4(KIF5A):​c.*1226C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 154,312 control chromosomes in the GnomAD database, including 6,394 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6316 hom., cov: 32)
  • Exomes 𝑓: 0.24 (78 hom.)
• Consequence: KIF5A NM_004984.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.607
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.48 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.*1226C>G		3_prime_UTR	Exon 29 of 29	NP_004975.2
	KIF5A	NM_001354705.2		c.*1226C>G		3_prime_UTR	Exon 26 of 26	NP_001341634.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	ENST00000455537.7	TSL:1 MANE Select	c.*1226C>G		3_prime_UTR	Exon 29 of 29	ENSP00000408979.2
	KIF5A	ENST00000674619.1		c.*1226C>G		3_prime_UTR	Exon 30 of 30	ENSP00000502270.1
	KIF5A	ENST00000938849.1		c.*2228C>G		3_prime_UTR	Exon 28 of 28	ENSP00000608908.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39479 AN: 151956 Hom.: 6292 Cov.: 32

Gnomad AFR AF: 0.0931

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.243 AC: 543 AN: 2236 Hom.: 78 Cov.: 0 AF XY: 0.247 AC XY: 278 AN XY: 1126

African (AFR) AF: 0.0395 AC: 3 AN: 76

American (AMR) AF: 0.625 AC: 5 AN: 8

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.469 AC: 45 AN: 96

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.222 AC: 363 AN: 1632

European-Non Finnish (NFE) AF: 0.281 AC: 64 AN: 228

Other (OTH) AF: 0.326 AC: 62 AN: 190

GnomAD4 genome AF: 0.260 AC: 39526 AN: 152076 Hom.: 6316 Cov.: 32 AF XY: 0.272 AC XY: 20205 AN XY: 74342

African (AFR) AF: 0.0929 AC: 3856 AN: 41502

American (AMR) AF: 0.368 AC: 5625 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 928 AN: 3470

East Asian (EAS) AF: 0.479 AC: 2478 AN: 5170

South Asian (SAS) AF: 0.497 AC: 2394 AN: 4820

European-Finnish (FIN) AF: 0.402 AC: 4242 AN: 10546

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19049 AN: 67972

Other (OTH) AF: 0.272 AC: 574 AN: 2108

Alfa AF: 0.162 Hom.: 368

Bravo AF: 0.253

Asia WGS AF: 0.490 AC: 1704 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.88
DANN	Benign	0.41
PhyloP100		-0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1678536; hg19: chr12-57979190;