rs1441080561

Variant names:

• chr2-240760762-C-A
• rs1441080561
• NM_001244008.2:c.2347G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240760762-C-A
• chr2-240760762-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001244008.2(KIF1A):​c.2347G>T​(p.Asp783Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,450,204 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D783H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 9

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuropathy, hereditary sensory, type 2C

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• hereditary spastic paraplegia 30

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• PEHO syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensory and autonomic neuropathy type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2	c.2347G>T	p.Asp783Tyr	missense_variant	Exon 25 of 49	ENST00000498729.9	NP_001230937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9	c.2347G>T	p.Asp783Tyr	missense_variant	Exon 25 of 49	5	NM_001244008.2	ENSP00000438388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720726

African (AFR) AF: 0.00 AC: 0 AN: 32820

American (AMR) AF: 0.00 AC: 0 AN: 42566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 38896

South Asian (SAS) AF: 0.00 AC: 0 AN: 84278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107100

Other (OTH) AF: 0.00 AC: 0 AN: 59854

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF1A protein function. This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 774 of the KIF1A protein (p.Asp774Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 532863). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.0	.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.;L;.;.;.;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.0	.;D;D;.;.;.;.;.;.;.;.;.;D
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;D
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.0
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.43
gMVP		0.68
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs1441080561; hg19: chr2-241700179;