16-46660189-G-GTTTTTTT

Position:

• chr16-46660189-G-GTTTTTTT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_018206.6(VPS35):​c.*282_*283insAAAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (62 hom., cov: 0)
  • Exomes 𝑓: 0.096 (390 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.37

Genes affected

VPS35 (HGNC:13487): (VPS35 retromer complex component) This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP6: Variant 16-46660189-G-GTTTTTTT is Benign according to our data. Variant chr16-46660189-G-GTTTTTTT is described in ClinVar as [Benign]. Clinvar id is 2646486.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.*282_*283insAAAAAAA		3_prime_UTR_variant	17/17	ENST00000299138.12	NP_060676.2
VPS35	XM_005256045.4	c.*282_*283insAAAAAAA		3_prime_UTR_variant	15/15		XP_005256102.1
VPS35	XM_011523227.4	c.*282_*283insAAAAAAA		3_prime_UTR_variant	17/17		XP_011521529.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35	ENST00000299138.12	c.*282_*283insAAAAAAA		3_prime_UTR_variant	17/17	1	NM_018206.6	ENSP00000299138	P1
VPS35	ENST00000568784.6	c.*3343_*3344insAAAAAAA		3_prime_UTR_variant, NMD_transcript_variant	17/17	1		ENSP00000456274
VPS35	ENST00000647959.1	c.*2736_*2737insAAAAAAA		3_prime_UTR_variant, NMD_transcript_variant	18/18			ENSP00000497702

Frequencies

GnomAD3 genomes AF: 0.00 AC: 318 AN: 89478 Hom.: 61 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00339

Gnomad AMR AF: 0.00185

Gnomad ASJ AF: 0.00196

Gnomad EAS AF: 0.00220

Gnomad SAS AF: 0.000930

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.00431

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0956 AC: 821 AN: 8590 Hom.: 390 Cov.: 0 AF XY: 0.0937 AC XY: 413 AN XY: 4408

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.148

Gnomad4 ASJ exome AF: 0.0991

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.0638

Gnomad4 FIN exome AF: 0.0966

Gnomad4 NFE exome AF: 0.0968

Gnomad4 OTH exome AF: 0.0882

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00358 AC: 320 AN: 89492 Hom.: 62 Cov.: 0 AF XY: 0.00414 AC XY: 165 AN XY: 39890

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.00185

Gnomad4 ASJ AF: 0.00196

Gnomad4 EAS AF: 0.00221

Gnomad4 SAS AF: 0.000933

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.00452

Gnomad4 OTH AF: 0.00430

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

VPS35: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs369756092; hg19: chr16-46694101;