rs2888334

Variant names:

• chr12-57582864-C-G
• rs2888334
• NM_004984.4:c.3020+235C>G

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.3020+235C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 638,542 control chromosomes in the GnomAD database, including 38,175 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6970 hom., cov: 31)
  • Exomes 𝑓: 0.34 (31205 hom.)
• Consequence: KIF5A NM_004984.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04
• Publications: 6 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=-0.87).
• BP6: Variant 12-57582864-C-G is Benign according to our data. Variant chr12-57582864-C-G is described in ClinVar as Benign. ClinVar VariationId is 682878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5A	NM_004984.4	c.3020+235C>G		intron_variant	Intron 27 of 28	ENST00000455537.7	NP_004975.2
KIF5A	NM_001354705.2	c.2753+235C>G		intron_variant	Intron 24 of 25		NP_001341634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5A	ENST00000455537.7	c.3020+235C>G		intron_variant	Intron 27 of 28	1	NM_004984.4	ENSP00000408979.2

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44131 AN: 151898 Hom.: 6966 Cov.: 31

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.338 AC: 164569 AN: 486526 Hom.: 31205 Cov.: 5 AF XY: 0.345 AC XY: 89366 AN XY: 259154

African (AFR) AF: 0.198 AC: 2687 AN: 13560

American (AMR) AF: 0.404 AC: 10145 AN: 25108

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 4441 AN: 15094

East Asian (EAS) AF: 0.656 AC: 20762 AN: 31630

South Asian (SAS) AF: 0.476 AC: 23575 AN: 49558

European-Finnish (FIN) AF: 0.354 AC: 11130 AN: 31400

Middle Eastern (MID) AF: 0.227 AC: 480 AN: 2118

European-Non Finnish (NFE) AF: 0.285 AC: 82693 AN: 290484

Other (OTH) AF: 0.314 AC: 8656 AN: 27574

GnomAD4 genome AF: 0.291 AC: 44162 AN: 152016 Hom.: 6970 Cov.: 31 AF XY: 0.298 AC XY: 22165 AN XY: 74280

African (AFR) AF: 0.205 AC: 8495 AN: 41474

American (AMR) AF: 0.333 AC: 5082 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 994 AN: 3470

East Asian (EAS) AF: 0.611 AC: 3146 AN: 5152

South Asian (SAS) AF: 0.483 AC: 2327 AN: 4820

European-Finnish (FIN) AF: 0.373 AC: 3937 AN: 10542

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19259 AN: 67968

Other (OTH) AF: 0.270 AC: 570 AN: 2112

Alfa AF: 0.293 Hom.: 873

Bravo AF: 0.284

Asia WGS AF: 0.507 AC: 1762 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.25
DANN	Benign	0.55
PhyloP100		-1.0
PromoterAI		-0.0038	Neutral
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)		0.010		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: rs2888334; hg19: chr12-57976647;