16-19669224-T-C

Position:

• chr16-19669224-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000417362.7(VPS35L):​c.2286T>C​(p.Asp762=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,612,292 control chromosomes in the GnomAD database, including 91,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9467 hom., cov: 33)
  • Exomes 𝑓: 0.33 (82333 hom.)
• Consequence: VPS35L ENST00000417362.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10

Genes affected

VPS35L (HGNC:24641): (VPS35 endosomal protein sorting factor like) Involved in Golgi to plasma membrane transport and endocytic recycling. Located in endosome. Implicated in Ritscher-Schinzel syndrome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-19669224-T-C is Benign according to our data. Variant chr16-19669224-T-C is described in ClinVar as [Benign]. Clinvar id is 1259444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS35L	NM_020314.7	c.2286T>C	p.Asp762=	synonymous_variant	27/31	ENST00000417362.7	NP_064710.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS35L	ENST00000417362.7	c.2286T>C	p.Asp762=	synonymous_variant	27/31	1	NM_020314.7	ENSP00000395973	P1
VPS35L	ENST00000251143.9	c.2553T>C	p.Asp851=	synonymous_variant	27/31	1		ENSP00000251143
VPS35L	ENST00000543152.5	c.1533T>C	p.Asp511=	synonymous_variant	21/25	1		ENSP00000457973
VPS35L	ENST00000542263.5	c.2007T>C	p.Asp669=	synonymous_variant	24/28	2		ENSP00000442468

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52963 AN: 152044 Hom.: 9460 Cov.: 33

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.317

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.324

GnomAD3 exomes AF: 0.337 AC: 84626 AN: 251084 Hom.: 14623 AF XY: 0.337 AC XY: 45718 AN XY: 135688

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.290

Gnomad ASJ exome AF: 0.355

Gnomad EAS exome AF: 0.322

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.334 AC: 487120 AN: 1460130 Hom.: 82333 Cov.: 34 AF XY: 0.334 AC XY: 242294 AN XY: 726228

Gnomad4 AFR exome AF: 0.367

Gnomad4 AMR exome AF: 0.290

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.384

Gnomad4 SAS exome AF: 0.313

Gnomad4 FIN exome AF: 0.438

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.348 AC: 52996 AN: 152162 Hom.: 9467 Cov.: 33 AF XY: 0.354 AC XY: 26358 AN XY: 74390

Gnomad4 AFR AF: 0.368

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.317

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.465

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.321

Alfa AF: 0.333 Hom.: 16899

Bravo AF: 0.337

Asia WGS AF: 0.288 AC: 1006 AN: 3478

EpiCase AF: 0.324

EpiControl AF: 0.325

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.14
DANN	Benign	0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs957676; hg19: chr16-19680546; COSMIC: COSV51977357;