NM_001244008.2:c.4604C>T

Variant names:

• chr2-240722517-G-A
• rs141441058
• NM_001244008.2:c.4604C>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.4604C>T​(p.Ala1535Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,548,294 control chromosomes in the GnomAD database, including 55 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1535G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (53 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 2.66
• Publications: 6 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=0.0037439167).
• BP6: Variant 2-240722517-G-A is Benign according to our data. Variant chr2-240722517-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211288.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00446 (679/152284) while in subpopulation NFE AF = 0.00849 (577/68000). AF 95% confidence interval is 0.00791. There are 2 homozygotes in GnomAd4. There are 302 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.4604C>T	p.Ala1535Val	missense	Exon 43 of 49	NP_001230937.1	Q12756-3
	KIF1A	NM_001379631.1		c.4679C>T	p.Ala1560Val	missense	Exon 43 of 49	NP_001366560.1
	KIF1A	NM_001379642.1		c.4604C>T	p.Ala1535Val	missense	Exon 43 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.4604C>T	p.Ala1535Val	missense	Exon 43 of 49	ENSP00000438388.1	Q12756-3
	KIF1A	ENST00000460788.5	TSL:1	n.1161C>T		non_coding_transcript_exon	Exon 3 of 9
	KIF1A	ENST00000492812.6	TSL:1	n.3187C>T		non_coding_transcript_exon	Exon 10 of 16

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152166 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00848

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00379 AC: 572 AN: 151034 AF XY: 0.00369

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000477

Gnomad EAS exome AF: 0.000184

Gnomad FIN exome AF: 0.000866

Gnomad NFE exome AF: 0.00856

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00748 AC: 10446 AN: 1396010 Hom.: 53 Cov.: 32 AF XY: 0.00741 AC XY: 5104 AN XY: 688566

African (AFR) AF: 0.00127 AC: 40 AN: 31554

American (AMR) AF: 0.00118 AC: 42 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.000398 AC: 10 AN: 25132

East Asian (EAS) AF: 0.0000279 AC: 1 AN: 35874

South Asian (SAS) AF: 0.000379 AC: 30 AN: 79144

European-Finnish (FIN) AF: 0.00162 AC: 77 AN: 47436

Middle Eastern (MID) AF: 0.000430 AC: 2 AN: 4652

European-Non Finnish (NFE) AF: 0.00917 AC: 9890 AN: 1078748

Other (OTH) AF: 0.00612 AC: 354 AN: 57816

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152284 Hom.: 2 Cov.: 33 AF XY: 0.00406 AC XY: 302 AN XY: 74462

African (AFR) AF: 0.00142 AC: 59 AN: 41578

American (AMR) AF: 0.000784 AC: 12 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00849 AC: 577 AN: 68000

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

Alfa AF: 0.00615 Hom.: 2

Bravo AF: 0.00452

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00196 AC: 7

ESP6500EA AF: 0.00516 AC: 40

ExAC AF: 0.00150 AC: 140

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 30 (1)
-	-	1	History of neurodevelopmental disorder (1)
-	1	-	Intellectual disability, autosomal dominant 9 (1)
-	-	1	KIF1A-related 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	0.069
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.7
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.064
Sift	Benign	0.054	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.47
MPC		0.43
ClinPred		0.020	T
GERP RS		3.6
Varity_R		0.063
gMVP		0.31
Mutation Taster		=99/1	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: rs141441058; hg19: chr2-241661934; COSMIC: COSV57499175; COSMIC: COSV57499175;