rs75907338

chr12-57570045-G-Achr12-57570045-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004984.4(KIF5A):c.1176G>A(p.Glu392=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,006 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (109 hom.)
• Consequence: KIF5A NM_004984.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-57570045-G-A is Benign according to our data. Variant chr12-57570045-G-A is described in ClinVar as [Benign]. Clinvar id is 309938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4	c.1176G>A	p.Glu392=	synonymous_variant	12/29	ENST00000455537.7
KIF5A	NM_001354705.2	c.909G>A	p.Glu303=	synonymous_variant	9/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.1176G>A	p.Glu392=	synonymous_variant	12/29	1	NM_004984.4	P1

Frequencies

GnomAD3 genomes AF: 0.00305 AC: 464 AN: 152256 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0699

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00587 AC: 1471 AN: 250742 Hom.: 56 AF XY: 0.00539 AC XY: 731 AN XY: 135624

Gnomad AFR exome AF: 0.000742

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0753

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00201 AC: 2931 AN: 1461632 Hom.: 109 Cov.: 32 AF XY: 0.00190 AC XY: 1380 AN XY: 727066

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0576

Gnomad4 SAS exome AF: 0.000951

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00816

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152374 Hom.: 19 Cov.: 32 AF XY: 0.00331 AC XY: 247 AN XY: 74522

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0697

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.00291

Asia WGS AF: 0.0700 AC: 243 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2016	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. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hereditary spastic paraplegia 10 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 09, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	11
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs75907338; hg19: chr12-57963828; COSMIC: COSV54058219;