rs775322

Variant names:

• chr12-57564530-A-G
• rs775322
• NM_004984.4:c.445+22A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-57564530-A-G
• chr12-57564530-A-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.445+22A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,577,814 control chromosomes in the GnomAD database, including 137,947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14309 hom., cov: 32)
  • Exomes 𝑓: 0.40 (123638 hom.)
• Consequence: KIF5A NM_004984.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0400
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-57564530-A-G is Benign according to our data. Variant chr12-57564530-A-G is described in ClinVar as Benign. ClinVar VariationId is 682854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 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.445+22A>G		intron	N/A	NP_004975.2
	KIF5A	NM_001354705.2		c.178+22A>G		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.445+22A>G		intron	N/A	ENSP00000408979.2	Q12840
	KIF5A	ENST00000674619.1		c.445+22A>G		intron	N/A	ENSP00000502270.1	A0A6Q8PGJ3
	KIF5A	ENST00000938849.1		c.445+22A>G		intron	N/A	ENSP00000608908.1

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64539 AN: 151884 Hom.: 14270 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.605

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.395

GnomAD2 exomes AF: 0.469 AC: 117745 AN: 251074 AF XY: 0.469

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.369

Gnomad EAS exome AF: 0.787

Gnomad FIN exome AF: 0.534

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.416

GnomAD4 exome AF: 0.403 AC: 575124 AN: 1425812 Hom.: 123638 Cov.: 29 AF XY: 0.408 AC XY: 290600 AN XY: 711536

African (AFR) AF: 0.417 AC: 13620 AN: 32650

American (AMR) AF: 0.508 AC: 22704 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 9692 AN: 25926

East Asian (EAS) AF: 0.788 AC: 31078 AN: 39426

South Asian (SAS) AF: 0.587 AC: 50054 AN: 85266

European-Finnish (FIN) AF: 0.519 AC: 27696 AN: 53378

Middle Eastern (MID) AF: 0.340 AC: 1935 AN: 5684

European-Non Finnish (NFE) AF: 0.364 AC: 393509 AN: 1079722

Other (OTH) AF: 0.420 AC: 24836 AN: 59080

GnomAD4 genome AF: 0.425 AC: 64632 AN: 152002 Hom.: 14309 Cov.: 32 AF XY: 0.437 AC XY: 32493 AN XY: 74290

African (AFR) AF: 0.423 AC: 17514 AN: 41440

American (AMR) AF: 0.439 AC: 6700 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1275 AN: 3466

East Asian (EAS) AF: 0.771 AC: 3986 AN: 5172

South Asian (SAS) AF: 0.605 AC: 2919 AN: 4822

European-Finnish (FIN) AF: 0.538 AC: 5690 AN: 10572

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.370 AC: 25153 AN: 67952

Other (OTH) AF: 0.401 AC: 846 AN: 2108

Alfa AF: 0.380 Hom.: 15291

Bravo AF: 0.418

Asia WGS AF: 0.658 AC: 2285 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 10 (1)
-	-	1	Myoclonus, intractable, neonatal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.33
PhyloP100		0.040
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs775322; hg19: chr12-57958313;