rs553976598

Positions:

chr2-240745878-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting

The NM_001244008.2(KIF1A):c.3234C>A(p.Ser1078Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,611,308 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).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.0110

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.09592956).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000184 (28/152320) while in subpopulation AMR AF= 0.00124 (19/15308). AF 95% confidence interval is 0.000812. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.3234C>A	p.Ser1078Arg	missense_variant	31/49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.3234C>A	p.Ser1078Arg	missense_variant	31/49	5	NM_001244008.2	ENSP00000438388		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.0000588

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000657

AC:

AN:

243348

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

132524

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000352

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000675

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1458988

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

725510

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000450

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000184

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.000306

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2018

The p.S977R variant (also known as c.2931C>A), located in coding exon 28 of the KIF1A gene, results from a C to A substitution at nucleotide position 2931. The serine at codon 977 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Intellectual disability, autosomal dominant 9

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 21, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 06, 2023

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;.;.;.;.;D;.;.;.;.;.;.

Eigen

Benign

-0.091

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.92

.;D;D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.054

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.;.;M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.6

.;D;D;.;.;.;.;.;.;.;.;.;.;D

REVEL

Uncertain

0.38

Sift

Uncertain

0.018

.;D;D;.;.;.;.;.;.;.;.;.;.;D

Sift4G

Benign

0.14

.;T;T;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.39

B;.;.;.;.;.;.;B;.;.;.;.;.;P

Vest4

0.63, 0.58

MutPred

0.22

Gain of solvent accessibility (P = 0.0314);.;Gain of solvent accessibility (P = 0.0314);.;.;Gain of solvent accessibility (P = 0.0314);.;Gain of solvent accessibility (P = 0.0314);Gain of solvent accessibility (P = 0.0314);.;.;.;.;.;

MVP

0.81

MPC

0.95

ClinPred

0.28

GERP RS

4.3

Varity_R

0.25

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over