rs181688415

Positions:

• chr12-57569237-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004984.4(KIF5A):​c.820-19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,613,140 control chromosomes in the GnomAD database, including 133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (126 hom.)
• Consequence: KIF5A NM_004984.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0940

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 12-57569237-G-T is Benign according to our data. Variant chr12-57569237-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 382750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-57569237-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00732 (1111/151796) while in subpopulation NFE AF= 0.0126 (854/67962). AF 95% confidence interval is 0.0119. There are 7 homozygotes in gnomad4. There are 526 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF5A	NM_004984.4	c.820-19G>T		intron_variant		ENST00000455537.7
KIF5A	NM_001354705.2	c.553-19G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF5A	ENST00000455537.7	c.820-19G>T		intron_variant		1	NM_004984.4	P1
KIF5A	ENST00000286452.5	c.553-19G>T		intron_variant		2
KIF5A	ENST00000674619.1	c.820-19G>T		intron_variant
KIF5A	ENST00000676457.1	c.715-19G>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1111 AN: 151678 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00277

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00605

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00789 AC: 1982 AN: 251304 Hom.: 16 AF XY: 0.00844 AC XY: 1146 AN XY: 135838

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00683

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.0115 AC: 16876 AN: 1461344 Hom.: 126 Cov.: 32 AF XY: 0.0116 AC XY: 8416 AN XY: 727030

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00753

Gnomad4 FIN exome AF: 0.00802

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.00956

GnomAD4 genome AF: 0.00732 AC: 1111 AN: 151796 Hom.: 7 Cov.: 32 AF XY: 0.00709 AC XY: 526 AN XY: 74144

Gnomad4 AFR AF: 0.00174

Gnomad4 AMR AF: 0.00276

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00605

Gnomad4 FIN AF: 0.00904

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00983 Hom.: 0

Bravo AF: 0.00649

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 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

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.1
DANN	Benign	0.75

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: rs181688415; hg19: chr12-57963020;