rs764873243

Positions:

• chr2-240746137-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BP6

The NM_001244008.2(KIF1A):​c.3104C>T​(p.Ser1035Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000153 in 1,569,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1035S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.72

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 -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KIF1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.28528804).
• BP6: Variant 2-240746137-G-A is Benign according to our data. Variant chr2-240746137-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435628.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.3104C>T	p.Ser1035Leu	missense_variant	30/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.3104C>T	p.Ser1035Leu	missense_variant	30/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000281 AC: 5 AN: 177890 Hom.: 0 AF XY: 0.0000314 AC XY: 3 AN XY: 95454

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000793

Gnomad SAS exome AF: 0.0000418

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000402

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 21 AN: 1417622 Hom.: 0 Cov.: 32 AF XY: 0.0000171 AC XY: 12 AN XY: 701192

Gnomad4 AFR exome AF: 0.0000925

Gnomad4 AMR exome AF: 0.0000263

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000539

Gnomad4 SAS exome AF: 0.0000373

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000917

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74440

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000842 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 03, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Aug 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
Polyphen		0.82	P;.;.;.;.;.;.;P;.;.;.;.;P
Vest4		0.29, 0.23
MutPred		0.23		Loss of glycosylation at S934 (P = 0.0289);.;Loss of glycosylation at S934 (P = 0.0289);.;.;Loss of glycosylation at S934 (P = 0.0289);.;Loss of glycosylation at S934 (P = 0.0289);Loss of glycosylation at S934 (P = 0.0289);.;.;.;.;
MVP		0.57
MPC		0.59
ClinPred		0.84	D
GERP RS		4.6
Varity_R		0.24
gMVP		0.70

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: rs764873243; hg19: chr2-241685554; COSMIC: COSV57485399; COSMIC: COSV57485399;