chr16-19669224-T-C

Variant names:

• chr16-19669224-T-C
• rs957676
• NM_020314.7:c.2286T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020314.7(VPS35L):​c.2286T>C​(p.Asp762Asp) 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 NM_020314.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10
• Publications: 15 publications found

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]

VPS35L Gene-Disease associations (from GenCC):

• Ritscher-Schinzel syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
• Ritscher-Schinzel syndrome 3

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020314.7. 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
	VPS35L	NM_020314.7	MANE Select	c.2286T>C	p.Asp762Asp	synonymous	Exon 27 of 31	NP_064710.5
	VPS35L	NM_001365293.2		c.2208T>C	p.Asp736Asp	synonymous	Exon 26 of 30	NP_001352222.1
	VPS35L	NM_001365294.2		c.2085T>C	p.Asp695Asp	synonymous	Exon 25 of 29	NP_001352223.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35L	ENST00000417362.7	TSL:1 MANE Select	c.2286T>C	p.Asp762Asp	synonymous	Exon 27 of 31	ENSP00000395973.3	Q7Z3J2-1
	VPS35L	ENST00000251143.9	TSL:1	c.2553T>C	p.Asp851Asp	synonymous	Exon 27 of 31	ENSP00000251143.6	E7EWW0
	VPS35L	ENST00000543152.5	TSL:1	c.1533T>C	p.Asp511Asp	synonymous	Exon 21 of 25	ENSP00000457973.1	H3BV68

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

GnomAD2 exomes AF: 0.337 AC: 84626 AN: 251084 AF XY: 0.337

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 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

African (AFR) AF: 0.367 AC: 12275 AN: 33444

American (AMR) AF: 0.290 AC: 12957 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9213 AN: 26106

East Asian (EAS) AF: 0.384 AC: 15217 AN: 39662

South Asian (SAS) AF: 0.313 AC: 26938 AN: 86060

European-Finnish (FIN) AF: 0.438 AC: 23297 AN: 53242

Middle Eastern (MID) AF: 0.306 AC: 1763 AN: 5768

European-Non Finnish (NFE) AF: 0.329 AC: 365827 AN: 1110852

Other (OTH) AF: 0.326 AC: 19633 AN: 60312

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

African (AFR) AF: 0.368 AC: 15264 AN: 41510

American (AMR) AF: 0.317 AC: 4849 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1256 AN: 3468

East Asian (EAS) AF: 0.317 AC: 1644 AN: 5178

South Asian (SAS) AF: 0.292 AC: 1408 AN: 4830

European-Finnish (FIN) AF: 0.465 AC: 4913 AN: 10574

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22692 AN: 67998

Other (OTH) AF: 0.321 AC: 679 AN: 2112

Alfa AF: 0.335 Hom.: 26088

Bravo AF: 0.337

Asia WGS AF: 0.288 AC: 1006 AN: 3478

EpiCase AF: 0.324

EpiControl AF: 0.325

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.14
DANN	Benign	0.50
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism (auto)

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