12-57569403-C-T

Variant names:

• chr12-57569403-C-T
• rs1012819766
• NM_004984.4:c.967C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_004984.4(KIF5A):​c.967C>T​(p.Arg323Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 15/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KIF5A NM_004984.4 missense, splice_region
• Scores: Splicing: ADA: 0.9964
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 0.343
• Publications: 10 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: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-57569404-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1406446.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 12-57569403-C-T is Pathogenic according to our data. Variant chr12-57569403-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 409666.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.967C>T	p.Arg323Trp	missense splice_region	Exon 10 of 29	NP_004975.2
	KIF5A	NM_001354705.2		c.700C>T	p.Arg234Trp	missense splice_region	Exon 7 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.967C>T	p.Arg323Trp	missense splice_region	Exon 10 of 29	ENSP00000408979.2	Q12840
	KIF5A	ENST00000674619.1		c.967C>T	p.Arg323Trp	missense splice_region	Exon 10 of 30	ENSP00000502270.1	A0A6Q8PGJ3
	KIF5A	ENST00000938849.1		c.967C>T	p.Arg323Trp	missense splice_region	Exon 10 of 28	ENSP00000608908.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74280

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary spastic paraplegia 10 (3)
3	-	-	not provided (3)
-	1	-	Hereditary spastic paraplegia (1)
1	-	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		0.34
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.82		Loss of disorder (P = 0.0135)
MVP		0.95
MPC		2.6
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.97
gMVP		0.98
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.17		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: rs1012819766; hg19: chr12-57963186; COSMIC: COSV54059248;