rs3743928

Variant names:

• chr16-46689167-C-T
• rs3743928
• NM_018206.6:c.-34G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-46689167-C-T
• chr16-46689167-C-A
• chr16-46689167-C-G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_018206.6(VPS35):​c.-34G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,603,544 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (15 hom.)
• Consequence: VPS35 NM_018206.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.355
• Publications: 6 publications found

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]

ORC6 (HGNC:17151): (origin recognition complex subunit 6) The origin recognition complex (ORC) is a highly conserved six subunit protein complex essential for the initiation of the DNA replication in eukaryotic cells. Studies in yeast demonstrated that ORC binds specifically to origins of replication and serves as a platform for the assembly of additional initiation factors such as Cdc6 and Mcm proteins. The protein encoded by this gene is a subunit of the ORC complex. Gene silencing studies with small interfering RNA demonstrated that this protein plays an essential role in coordinating chromosome replication and segregation with cytokinesis. [provided by RefSeq, Oct 2010]

ORC6 Gene-Disease associations (from GenCC):

• Meier-Gorlin syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Meier-Gorlin syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 16-46689167-C-T is Benign according to our data. Variant chr16-46689167-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00158 (240/152336) while in subpopulation EAS AF = 0.0274 (142/5182). AF 95% confidence interval is 0.0237. There are 4 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018206.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35	NM_018206.6	MANE Select	c.-34G>A		5_prime_UTR	Exon 1 of 17	NP_060676.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35	ENST00000299138.12	TSL:1 MANE Select	c.-34G>A		5_prime_UTR	Exon 1 of 17	ENSP00000299138.7	Q96QK1
	VPS35	ENST00000921303.1		c.-34G>A		5_prime_UTR	Exon 1 of 17	ENSP00000591362.1
	VPS35	ENST00000904865.1		c.-34G>A		5_prime_UTR	Exon 1 of 17	ENSP00000574924.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 238 AN: 152218 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00328 AC: 725 AN: 220946 AF XY: 0.00310

Gnomad AFR exome AF: 0.0000750

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00108

Gnomad EAS exome AF: 0.0295

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.000646

Gnomad OTH exome AF: 0.00313

GnomAD4 exome AF: 0.00122 AC: 1766 AN: 1451208 Hom.: 15 Cov.: 31 AF XY: 0.00117 AC XY: 843 AN XY: 720912

African (AFR) AF: 0.000180 AC: 6 AN: 33354

American (AMR) AF: 0.00224 AC: 98 AN: 43660

Ashkenazi Jewish (ASJ) AF: 0.00101 AC: 26 AN: 25802

East Asian (EAS) AF: 0.0238 AC: 933 AN: 39140

South Asian (SAS) AF: 0.00135 AC: 114 AN: 84396

European-Finnish (FIN) AF: 0.00192 AC: 98 AN: 51050

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5696

European-Non Finnish (NFE) AF: 0.000242 AC: 268 AN: 1108168

Other (OTH) AF: 0.00369 AC: 221 AN: 59942

GnomAD4 genome AF: 0.00158 AC: 240 AN: 152336 Hom.: 4 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.00189 AC: 29 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.0274 AC: 142 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000879 Hom.: 1

Bravo AF: 0.00210

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Meier-Gorlin syndrome (1)
-	-	1	not provided (1)
-	-	1	Parkinson disease 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		-0.35
PromoterAI		-0.45	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=299/1	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: rs3743928; hg19: chr16-46723079;