1-10232338-G-T

Variant names:

• chr1-10232338-G-T
• rs371015089
• NM_001365951.3:c.10G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365951.3(KIF1B):​c.10G>T​(p.Ala4Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.04
• Publications: 1 publications found

Genes affected

KIF1B (HGNC:16636): (kinesin family member 1B) Predicted to enable microtubule binding activity and plus-end-directed microtubule motor activity. Predicted to be involved in chemical synaptic transmission; dense core granule cytoskeletal transport; and vesicle-mediated transport. Predicted to act upstream of or within mitochondrion transport along microtubule. Predicted to be located in cytoplasmic vesicle membrane and neuron projection. Predicted to be part of kinesin complex. Predicted to be active in several cellular components, including axon; dendrite; and microtubule. Implicated in Charcot-Marie-Tooth disease type 2A1; carcinoma (multiple); multiple sclerosis; neuroblastoma; and pheochromocytoma. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

KIF1B Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 2A1

  Inheritance: AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuroblastoma, susceptibility to, 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18626875).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.10G>T	p.Ala4Ser	missense_variant	Exon 2 of 49	ENST00000676179.1	NP_001352880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.10G>T	p.Ala4Ser	missense_variant	Exon 2 of 49		NM_001365951.3	ENSP00000502065.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A4S variant (also known as c.10G>T), located in coding exon 1 of the KIF1B gene, results from a G to T substitution at nucleotide position 10. The alanine at codon 4 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.13	.;.;T;.;.;.;.
Eigen	Benign	-0.052
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.29	N;N;N;N;N;.;.
PhyloP100		9.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N;N;N;N;N;.;.
REVEL	Benign	0.28
Sift	Benign	0.51	T;T;T;T;T;.;.
Sift4G	Benign	0.61	T;T;T;T;T;T;T
Polyphen		0.20	B;P;B;B;.;P;.
Vest4		0.54
MutPred		0.28		Gain of phosphorylation at A4 (P = 0.0203);Gain of phosphorylation at A4 (P = 0.0203);Gain of phosphorylation at A4 (P = 0.0203);Gain of phosphorylation at A4 (P = 0.0203);Gain of phosphorylation at A4 (P = 0.0203);Gain of phosphorylation at A4 (P = 0.0203);Gain of phosphorylation at A4 (P = 0.0203);
MVP		0.63
MPC		1.9
ClinPred		0.55	D
GERP RS		5.4
PromoterAI		0.00040	Neutral
Varity_R		0.22
gMVP		0.36
Mutation Taster		=59/41	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: rs371015089; hg19: chr1-10292396;