12-57581428-G-A

Position:

• chr12-57581428-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004984.4(KIF5A):​c.2769G>A​(p.Arg923=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,613,844 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (37 hom.)
• Consequence: KIF5A NM_004984.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.383

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 12-57581428-G-A is Benign according to our data. Variant chr12-57581428-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 215507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57581428-G-A is described in Lovd as [Likely_benign]. Variant chr12-57581428-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0039 (593/152114) while in subpopulation NFE AF= 0.00666 (453/67990). AF 95% confidence interval is 0.00616. There are 3 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 593 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4	c.2769G>A	p.Arg923=	synonymous_variant	25/29	ENST00000455537.7
KIF5A	NM_001354705.2	c.2502G>A	p.Arg834=	synonymous_variant	22/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.2769G>A	p.Arg923=	synonymous_variant	25/29	1	NM_004984.4	P1

Frequencies

GnomAD3 genomes AF: 0.00389 AC: 592 AN: 151996 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000662

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00404 AC: 1015 AN: 251186 Hom.: 2 AF XY: 0.00416 AC XY: 565 AN XY: 135764

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00713

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00600 AC: 8764 AN: 1461730 Hom.: 37 Cov.: 34 AF XY: 0.00591 AC XY: 4294 AN XY: 727178

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00282

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00730

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00390 AC: 593 AN: 152114 Hom.: 3 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74358

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000662

Gnomad4 NFE AF: 0.00666

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00526 Hom.: 3

Bravo AF: 0.00413

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KIF5A: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2018	- -

Hereditary spastic paraplegia 10 Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary spastic paraplegia 10;C4310658:Myoclonus, intractable, neonatal;C4693609:Amyotrophic lateral sclerosis, susceptibility to, 25 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 17, 2022

- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.7
DANN	Benign	0.69

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: rs35225609; hg19: chr12-57975211;