2-240713870-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001244008.2(KIF1A):c.*3494T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,820 control chromosomes in the GnomAD database, including 18,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.47 (18291 hom., cov: 34)
  • Exomes 𝑓: 0.35 (36 hom.)
• Consequence: KIF1A NM_001244008.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.159

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-240713870-A-G is Benign according to our data. Variant chr2-240713870-A-G is described in ClinVar as [Benign]. Clinvar id is 335210.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.*3494T>C		3_prime_UTR_variant	49/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.*3494T>C		3_prime_UTR_variant	49/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70787 AN: 152056 Hom.: 18248 Cov.: 34

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.448

Gnomad AMR AF: 0.519

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.466

GnomAD4 exome AF: 0.348 AC: 225 AN: 646 Hom.: 36 Cov.: 0 AF XY: 0.364 AC XY: 139 AN XY: 382

Gnomad4 AFR exome AF: 1.00

Gnomad4 AMR exome AF: 1.00

Gnomad4 EAS exome AF: 0.341

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.337

Gnomad4 NFE exome AF: 0.365

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.466 AC: 70886 AN: 152174 Hom.: 18291 Cov.: 34 AF XY: 0.464 AC XY: 34545 AN XY: 74406

Gnomad4 AFR AF: 0.691

Gnomad4 AMR AF: 0.519

Gnomad4 ASJ AF: 0.521

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.399

Gnomad4 NFE AF: 0.357

Gnomad4 OTH AF: 0.465

Alfa AF: 0.391 Hom.: 11303

Bravo AF: 0.490

Asia WGS AF: 0.290 AC: 1014 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 30 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.41
Dann	Benign	0.35

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: rs4613; hg19: chr2-241653287; COSMIC: COSV57494241; COSMIC: COSV57494241;