rs35225609

Variant names:

• chr12-57581428-G-A
• rs35225609
• NM_004984.4:c.2769G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57581428-G-A
• chr12-57581428-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004984.4(KIF5A):​c.2769G>A​(p.Arg923Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,613,844 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (37 hom.)
• Consequence: KIF5A NM_004984.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.383
• Publications: 0 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: Illumina, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary spastic paraplegia 10

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-57581428-G-A is Benign according to our data. Variant chr12-57581428-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0039 (593/152114) while in subpopulation NFE AF = 0.00666 (453/67990). AF 95% confidence interval is 0.00616. There are 3 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 593 AD gene.

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.2769G>A	p.Arg923Arg	synonymous	Exon 25 of 29	NP_004975.2
	KIF5A	NM_001354705.2		c.2502G>A	p.Arg834Arg	synonymous	Exon 22 of 26	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.2769G>A	p.Arg923Arg	synonymous	Exon 25 of 29	ENSP00000408979.2	Q12840
	KIF5A	ENST00000674619.1		c.2790G>A	p.Arg930Arg	synonymous	Exon 26 of 30	ENSP00000502270.1	A0A6Q8PGJ3
	KIF5A	ENST00000938849.1		c.2769G>A	p.Arg923Arg	synonymous	Exon 25 of 28	ENSP00000608908.1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 151996 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000662

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00404 AC: 1015 AN: 251186 AF XY: 0.00416

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00713

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00600 AC: 8764 AN: 1461730 Hom.: 37 Cov.: 34 AF XY: 0.00591 AC XY: 4294 AN XY: 727178

African (AFR) AF: 0.000896 AC: 30 AN: 33480

American (AMR) AF: 0.00282 AC: 126 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00108 AC: 93 AN: 86256

European-Finnish (FIN) AF: 0.00120 AC: 64 AN: 53264

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.00730 AC: 8116 AN: 1112006

Other (OTH) AF: 0.00462 AC: 279 AN: 60396

GnomAD4 genome AF: 0.00390 AC: 593 AN: 152114 Hom.: 3 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74358

African (AFR) AF: 0.00133 AC: 55 AN: 41494

American (AMR) AF: 0.00393 AC: 60 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4808

European-Finnish (FIN) AF: 0.000662 AC: 7 AN: 10582

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00666 AC: 453 AN: 67990

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.00526 Hom.: 3

Bravo AF: 0.00413

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Hereditary spastic paraplegia 10 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 10;C4310658:Myoclonus, intractable, neonatal;C4693609:Amyotrophic lateral sclerosis, susceptibility to, 25 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.7
DANN	Benign	0.69
PhyloP100		-0.38
PromoterAI		-0.025	Neutral
Mutation Taster		=90/10	polymorphism

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: rs35225609; hg19: chr12-57975211;