rs1553167616

Positions:

• chr1-10324829-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP2 BP4_Moderate BP6

The NM_001365951.3(KIF1B):​c.2609G>A​(p.Ser870Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. S870G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1B. . Gene score misZ 3.599 (greater than the threshold 3.09). Trascript score misZ 5.2436 (greater than threshold 3.09). GenCC has associacion of gene with pheochromocytoma, neuroblastoma, susceptibility to, 1, hereditary pheochromocytoma-paraganglioma, Charcot-Marie-Tooth disease type 2A1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06969306).
• BP6: Variant 1-10324829-G-A is Benign according to our data. Variant chr1-10324829-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 543214.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.2609G>A	p.Ser870Asn	missense_variant	26/49	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1	c.2609G>A	p.Ser870Asn	missense_variant	26/49		NP_001352881.1
KIF1B	NM_015074.3	c.2471G>A	p.Ser824Asn	missense_variant	24/47		NP_055889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.2609G>A	p.Ser870Asn	missense_variant	26/49		NM_001365951.3	ENSP00000502065.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with KIF1B-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with asparagine at codon 824 of the KIF1B protein (p.Ser824Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.095	.;T;.;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.070	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	.;N;N;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.74	N;N;N;.;.
REVEL	Benign	0.092
Sift	Benign	0.68	T;T;T;.;.
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.0	B;B;.;B;.
Vest4		0.22
MutPred		0.25		.;Loss of glycosylation at S870 (P = 0.0321);Loss of glycosylation at S870 (P = 0.0321);.;.;
MVP		0.47
MPC		0.38
ClinPred		0.17	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553167616; hg19: chr1-10384887;