rs374244985

chr2-240741338-G-Achr2-240741338-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001244008.2(KIF1A):c.3680C>T(p.Pro1227Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,593,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1227Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 5.72

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KIF1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.022413999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.3680C>T	p.Pro1227Leu	missense_variant	35/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.3680C>T	p.Pro1227Leu	missense_variant	35/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000211 AC: 46 AN: 218374 Hom.: 0 AF XY: 0.000210 AC XY: 25 AN XY: 119068

Gnomad AFR exome AF: 0.0000772

Gnomad AMR exome AF: 0.0000622

Gnomad ASJ exome AF: 0.000942

Gnomad EAS exome AF: 0.000904

Gnomad SAS exome AF: 0.000181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 175 AN: 1441292 Hom.: 1 Cov.: 31 AF XY: 0.000136 AC XY: 97 AN XY: 715806

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000210

Gnomad4 ASJ exome AF: 0.00104

Gnomad4 EAS exome AF: 0.000384

Gnomad4 SAS exome AF: 0.000191

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000859

Gnomad4 OTH exome AF: 0.000201

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74470

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.000257 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 25, 2019	The KIF1A c.3377C>T; p.Pro1126Leu variant (rs374244985), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 447653). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.1 percent in the Ashkenazi Jewish population (identified on 49 out of 249,768 chromosomes). The proline at position 1126 is weakly conserved and computational analyses of the effects of the p.Pro1126Leu variant on protein structure and function is neutral (SIFT: tolerated, PolyPhen-2: benign). Overall, there is not enough evidence to classify the p.Pro1126Leu variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2020

The p.P1227L variant (also known as c.3680C>T), located in coding exon 34 of the KIF1A gene, results from a C to T substitution at nucleotide position 3680. The proline at codon 1227 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 30 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Neuropathy, hereditary sensory and autonomic, type 2A;C3280168:Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.18	T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.022	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N;.;.;.;.;.;.;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
Polyphen		0.17	B;.;.;.;.;.;.;B;.;.;.;.;.;B
Vest4		0.46, 0.45
MVP		0.56
MPC		0.46
ClinPred		0.043	T
GERP RS		4.3
Varity_R		0.061
gMVP		0.24

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: rs374244985; hg19: chr2-241680755;