20-2840754-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_022575.4(VPS16):c.-21C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0603 in 1,547,656 control chromosomes in the GnomAD database, including 3,124 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.053 (273 hom., cov: 33)
  • Exomes 𝑓: 0.061 (2851 hom.)
• Consequence: VPS16 NM_022575.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.117

Genes affected

VPS16 (HGNC:14584): (VPS16 core subunit of CORVET and HOPS complexes) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene encodes the human homolog of yeast class C Vps16 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

PCED1A (HGNC:16212): (PC-esterase domain containing 1A) The protein encoded by this gene is a member of the GDSL/SGNH superfamily. Members of this family are hydrolytic enzymes with esterase and lipase activity and broad substrate specificity. This protein belongs to the Pmr5-Cas1p-esterase subfamily in that it contains the catalytic triad comprised of serine, aspartate and histidine and lacks two conserved regions (glycine after strand S2 and GxND motif). A pseudogene of this gene has been identified on the long arm of chromosome 2. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Sep 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 20-2840754-C-T is Benign according to our data. Variant chr20-2840754-C-T is described in ClinVar as [Benign]. Clinvar id is 1268336.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS16	NM_022575.4	c.-21C>T		5_prime_UTR_variant	1/24	ENST00000380445.8
VPS16	NM_080413.3	c.-21C>T		5_prime_UTR_variant	1/20
PCED1A	NM_001271168.2	c.-22+112G>A		intron_variant
PCED1A	XM_005260804.3	c.-22+112G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS16	ENST00000380445.8	c.-21C>T		5_prime_UTR_variant	1/24	1	NM_022575.4	P1

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 8008 AN: 152216 Hom.: 272 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.0588

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0676

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0659

Gnomad OTH AF: 0.0707

GnomAD3 exomes AF: 0.0534 AC: 8146 AN: 152572 Hom.: 273 AF XY: 0.0522 AC XY: 4225 AN XY: 80908

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.0412

Gnomad ASJ exome AF: 0.0417

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.0200

Gnomad FIN exome AF: 0.0633

Gnomad NFE exome AF: 0.0658

Gnomad OTH exome AF: 0.0567

GnomAD4 exome AF: 0.0611 AC: 85257 AN: 1395322 Hom.: 2851 Cov.: 31 AF XY: 0.0599 AC XY: 41227 AN XY: 688248

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.0421

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.0219

Gnomad4 FIN exome AF: 0.0633

Gnomad4 NFE exome AF: 0.0649

Gnomad4 OTH exome AF: 0.0594

GnomAD4 genome AF: 0.0526 AC: 8015 AN: 152334 Hom.: 273 Cov.: 33 AF XY: 0.0534 AC XY: 3976 AN XY: 74488

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.0587

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.0211

Gnomad4 FIN AF: 0.0676

Gnomad4 NFE AF: 0.0660

Gnomad4 OTH AF: 0.0733

Alfa AF: 0.0482 Hom.: 33

Bravo AF: 0.0517

Asia WGS AF: 0.0540 AC: 187 AN: 3478

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

GeneDx

May 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	6.8
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2297046; hg19: chr20-2821400; COSMIC: COSV62314178; COSMIC: COSV62314178;