16-46660189-G-GTTTTTT

Position:

• chr16-46660189-G-GTTTTTT

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

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

• Frequency:
  • Genomes: 𝑓 0.0027 (52 hom., cov: 0)
  • Exomes 𝑓: 0.22 (897 hom.)
  • Failed GnomAD Quality Control
• Consequence: VPS35 NM_018206.6 3_prime_UTR
• Clinical Significance: Likely 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 -6 ACMG points.

• BP6: Variant 16-46660189-G-GTTTTTT is Benign according to our data. Variant chr16-46660189-G-GTTTTTT is described in ClinVar as [Likely_benign]. Clinvar id is 1711407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 245 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35	NM_018206.6	c.*282_*283insAAAAAA		3_prime_UTR_variant	17/17	ENST00000299138.12	NP_060676.2
VPS35	XM_005256045.4	c.*282_*283insAAAAAA		3_prime_UTR_variant	15/15		XP_005256102.1
VPS35	XM_011523227.4	c.*282_*283insAAAAAA		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_*283insAAAAAA		3_prime_UTR_variant	17/17	1	NM_018206.6	ENSP00000299138	P1
VPS35	ENST00000568784.6	c.*3343_*3344insAAAAAA		3_prime_UTR_variant, NMD_transcript_variant	17/17	1		ENSP00000456274
VPS35	ENST00000647959.1	c.*2736_*2737insAAAAAA		3_prime_UTR_variant, NMD_transcript_variant	18/18			ENSP00000497702

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 241 AN: 89586 Hom.: 50 Cov.: 0

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00167

Gnomad AMR AF: 0.00323

Gnomad ASJ AF: 0.00156

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00139

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.00258

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.217 AC: 1864 AN: 8590 Hom.: 897 Cov.: 0 AF XY: 0.216 AC XY: 954 AN XY: 4408

Gnomad4 AFR exome AF: 0.0678

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.314

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.229

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.00273 AC: 245 AN: 89600 Hom.: 52 Cov.: 0 AF XY: 0.00353 AC XY: 141 AN XY: 39942

Gnomad4 AFR AF: 0.00396

Gnomad4 AMR AF: 0.00322

Gnomad4 ASJ AF: 0.00156

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00140

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.00174

Gnomad4 OTH AF: 0.00257

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

VPS35: 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;