rs75413741

Variant names:

• chr1-10375007-A-G
• rs75413741
• NM_001365951.3:c.5250A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001365951.3(KIF1B):​c.5250A>G​(p.Ala1750Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,614,132 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (48 hom.)
• Consequence: KIF1B NM_001365951.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.15
• Publications: 4 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-10375007-A-G is Benign according to our data. Variant chr1-10375007-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.
• BS2: High AC in GnomAd4 at 623 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	NM_001365951.3	MANE Select	c.5250A>G	p.Ala1750Ala	synonymous	Exon 47 of 49	NP_001352880.1
	KIF1B	NM_001365952.1		c.5250A>G	p.Ala1750Ala	synonymous	Exon 47 of 49	NP_001352881.1
	KIF1B	NM_015074.3		c.5112A>G	p.Ala1704Ala	synonymous	Exon 45 of 47	NP_055889.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	ENST00000676179.1	MANE Select	c.5250A>G	p.Ala1750Ala	synonymous	Exon 47 of 49	ENSP00000502065.1
	KIF1B	ENST00000377081.5	TSL:1	c.5250A>G	p.Ala1750Ala	synonymous	Exon 46 of 48	ENSP00000366284.1
	KIF1B	ENST00000377086.5	TSL:1	c.5250A>G	p.Ala1750Ala	synonymous	Exon 47 of 49	ENSP00000366290.1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 623 AN: 152124 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00302

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00735

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00455 AC: 1144 AN: 251484 AF XY: 0.00481

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00434

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00539 AC: 7886 AN: 1461890 Hom.: 48 Cov.: 34 AF XY: 0.00540 AC XY: 3928 AN XY: 727248

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.00262 AC: 117 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86258

European-Finnish (FIN) AF: 0.00326 AC: 174 AN: 53420

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00647 AC: 7193 AN: 1112008

Other (OTH) AF: 0.00402 AC: 243 AN: 60396

GnomAD4 genome AF: 0.00409 AC: 623 AN: 152242 Hom.: 2 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74428

African (AFR) AF: 0.000650 AC: 27 AN: 41538

American (AMR) AF: 0.00314 AC: 48 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00302 AC: 32 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00735 AC: 500 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00662 Hom.: 4

Bravo AF: 0.00408

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.0108

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Neuroblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.56
DANN	Benign	0.46
PhyloP100		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75413741; hg19: chr1-10435065; COSMIC: COSV55807888;