rs143037290

Variant names:

• chr2-240745853-G-A
• rs143037290
• NM_001244008.2:c.3259C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-240745853-G-A
• chr2-240745853-G-C
• chr2-240745853-G-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001244008.2(KIF1A):​c.3259C>T​(p.Pro1087Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,612,358 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. P1087P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (30 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 3.39
• Publications: 7 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, G2P, Labcorp Genetics (formerly Invitae)
• syndromic intellectual disability

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

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

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006913662).
• BP6: Variant 2-240745853-G-A is Benign according to our data. Variant chr2-240745853-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196129.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0037 (563/152278) while in subpopulation NFE AF = 0.00591 (402/68006). AF 95% confidence interval is 0.00543. There are 0 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 30 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244008.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	NM_001244008.2	MANE Select	c.3259C>T	p.Pro1087Ser	missense	Exon 31 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.3334C>T	p.Pro1112Ser	missense	Exon 31 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.3232C>T	p.Pro1078Ser	missense	Exon 30 of 49	NP_001366571.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1A	ENST00000498729.9	TSL:5 MANE Select	c.3259C>T	p.Pro1087Ser	missense	Exon 31 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000675932.2		c.3259C>T	p.Pro1087Ser	missense	Exon 31 of 49	ENSP00000502786.2	A0A6Q8PHQ5
	KIF1A	ENST00000675314.2		c.3388C>T	p.Pro1130Ser	missense	Exon 32 of 50	ENSP00000502584.2	A0A6Q8PH56

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 562 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00368 AC: 901 AN: 244548 AF XY: 0.00387

Gnomad AFR exome AF: 0.00108

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00244

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00174

Gnomad NFE exome AF: 0.00562

Gnomad OTH exome AF: 0.00538

GnomAD4 exome AF: 0.00460 AC: 6714 AN: 1460080 Hom.: 30 Cov.: 32 AF XY: 0.00470 AC XY: 3412 AN XY: 726218

African (AFR) AF: 0.000687 AC: 23 AN: 33458

American (AMR) AF: 0.00296 AC: 132 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 61 AN: 26050

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00273 AC: 235 AN: 85958

European-Finnish (FIN) AF: 0.00249 AC: 132 AN: 52918

Middle Eastern (MID) AF: 0.00833 AC: 48 AN: 5764

European-Non Finnish (NFE) AF: 0.00524 AC: 5829 AN: 1111394

Other (OTH) AF: 0.00419 AC: 253 AN: 60320

GnomAD4 genome AF: 0.00370 AC: 563 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.00352 AC XY: 262 AN XY: 74448

African (AFR) AF: 0.000914 AC: 38 AN: 41556

American (AMR) AF: 0.00457 AC: 70 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00591 AC: 402 AN: 68006

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00466 Hom.: 3

Bravo AF: 0.00335

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000513 AC: 2

ESP6500EA AF: 0.00386 AC: 32

ExAC AF: 0.00371 AC: 448

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00577

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	not specified (3)
-	1	1	Hereditary spastic paraplegia 30 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.11
Sift	Benign	0.27	T
Sift4G	Benign	0.31	T
Polyphen		0.61	P
Vest4		0.24
MVP		0.49
MPC		0.44
ClinPred		0.0096	T
GERP RS		4.2
PromoterAI		-0.0046	Neutral
Varity_R		0.11
gMVP		0.65
Mutation Taster		=94/6	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: rs143037290; hg19: chr2-241685270; COSMIC: COSV99064878; COSMIC: COSV99064878;