chr12-57567514-C-G

Variant names:

• chr12-57567514-C-G
• rs1555177629
• NM_004984.4:c.610C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_004984.4(KIF5A):​c.610C>G​(p.Arg204Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 28)
• Consequence: KIF5A NM_004984.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.568
• 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_004984.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-57567514-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 424651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4	c.610C>G	p.Arg204Gly	missense_variant	Exon 8 of 29	ENST00000455537.7	NP_004975.2
KIF5A	NM_001354705.2	c.343C>G	p.Arg115Gly	missense_variant	Exon 5 of 26		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7	c.610C>G	p.Arg204Gly	missense_variant	Exon 8 of 29	1	NM_004984.4	ENSP00000408979.2
KIF5A	ENST00000674619.1	c.610C>G	p.Arg204Gly	missense_variant	Exon 8 of 30			ENSP00000502270.1
KIF5A	ENST00000676457.1	c.505C>G	p.Arg169Gly	missense_variant	Exon 7 of 28			ENSP00000501588.1
KIF5A	ENST00000286452.5	c.343C>G	p.Arg115Gly	missense_variant	Exon 5 of 26	2		ENSP00000286452.5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.5	H;.
PhyloP100		0.57
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.86		Gain of catalytic residue at H201 (P = 8e-04);.;
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.90
gMVP		0.99
Mutation Taster		=16/84	disease causing

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: rs1555177629; hg19: chr12-57961297; COSMIC: COSV54052618;