rs73102625

Positions:

• chr2-240746169-G-A
• chr2-240746169-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_001244008.2(KIF1A):​c.3072C>T​(p.Ser1024Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0563 in 1,562,738 control chromosomes in the GnomAD database, including 2,587 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (289 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2298 hom.)
• Consequence: KIF1A NM_001244008.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -6.23

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]

KIF1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-240746169-G-A is Benign according to our data. Variant chr2-240746169-G-A is described in ClinVar as [Benign]. Clinvar id is 129389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240746169-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.23 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.3072C>T	p.Ser1024Ser	synonymous_variant	30/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.3072C>T	p.Ser1024Ser	synonymous_variant	30/49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes AF: 0.0584 AC: 8891 AN: 152132 Hom.: 283 Cov.: 33

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.00733

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0605

Gnomad OTH AF: 0.0498

GnomAD3 exomes AF: 0.0475 AC: 8062 AN: 169706 Hom.: 217 AF XY: 0.0463 AC XY: 4200 AN XY: 90718

Gnomad AFR exome AF: 0.0799

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0555

Gnomad EAS exome AF: 0.00562

Gnomad SAS exome AF: 0.0354

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0606

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0560 AC: 79004 AN: 1410488 Hom.: 2298 Cov.: 33 AF XY: 0.0556 AC XY: 38761 AN XY: 696896

Gnomad4 AFR exome AF: 0.0751

Gnomad4 AMR exome AF: 0.0307

Gnomad4 ASJ exome AF: 0.0564

Gnomad4 EAS exome AF: 0.00406

Gnomad4 SAS exome AF: 0.0337

Gnomad4 FIN exome AF: 0.0487

Gnomad4 NFE exome AF: 0.0601

Gnomad4 OTH exome AF: 0.0557

GnomAD4 genome AF: 0.0585 AC: 8910 AN: 152250 Hom.: 289 Cov.: 33 AF XY: 0.0567 AC XY: 4221 AN XY: 74438

Gnomad4 AFR AF: 0.0749

Gnomad4 AMR AF: 0.0374

Gnomad4 ASJ AF: 0.0559

Gnomad4 EAS AF: 0.00715

Gnomad4 SAS AF: 0.0302

Gnomad4 FIN AF: 0.0498

Gnomad4 NFE AF: 0.0605

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0400 Hom.: 33

Bravo AF: 0.0594

Asia WGS AF: 0.0290 AC: 105 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary spastic paraplegia 30 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. -

KIF1A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.2
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs73102625; hg19: chr2-241685586;