rs181688415

Variant names:

• chr12-57569237-G-T
• rs181688415
• NM_004984.4:c.820-19G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004984.4(KIF5A):​c.820-19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,140 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (126 hom.)
• Consequence: KIF5A NM_004984.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0940
• 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: 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=-0.72).
• BP6: Variant 12-57569237-G-T is Benign according to our data. Variant chr12-57569237-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382750.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 = 0.00732 (1111/151796) while in subpopulation NFE AF = 0.0126 (854/67962). AF 95% confidence interval is 0.0119. There are 7 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1111 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	NM_004984.4	MANE Select	c.820-19G>T		intron	N/A	NP_004975.2
	KIF5A	NM_001354705.2		c.553-19G>T		intron	N/A	NP_001341634.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF5A	ENST00000455537.7	TSL:1 MANE Select	c.820-19G>T		intron	N/A	ENSP00000408979.2
	KIF5A	ENST00000674619.1		c.820-19G>T		intron	N/A	ENSP00000502270.1
	KIF5A	ENST00000676457.1		c.715-19G>T		intron	N/A	ENSP00000501588.1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1111 AN: 151678 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00277

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00605

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00789 AC: 1982 AN: 251304 AF XY: 0.00844

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.0115 AC: 16876 AN: 1461344 Hom.: 126 Cov.: 32 AF XY: 0.0116 AC XY: 8416 AN XY: 727030

African (AFR) AF: 0.00137 AC: 46 AN: 33474

American (AMR) AF: 0.00300 AC: 134 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00753 AC: 649 AN: 86242

European-Finnish (FIN) AF: 0.00802 AC: 428 AN: 53386

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0135 AC: 14955 AN: 1111548

Other (OTH) AF: 0.00956 AC: 577 AN: 60378

GnomAD4 genome AF: 0.00732 AC: 1111 AN: 151796 Hom.: 7 Cov.: 32 AF XY: 0.00709 AC XY: 526 AN XY: 74144

African (AFR) AF: 0.00174 AC: 72 AN: 41392

American (AMR) AF: 0.00276 AC: 42 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00605 AC: 29 AN: 4792

European-Finnish (FIN) AF: 0.00904 AC: 95 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 854 AN: 67962

Other (OTH) AF: 0.00428 AC: 9 AN: 2104

Alfa AF: 0.00983 Hom.: 0

Bravo AF: 0.00649

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.1
DANN	Benign	0.75
PhyloP100		-0.094
Mutation Taster		=100/0	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: rs181688415; hg19: chr12-57963020;