16-19583771-G-A

Variant names:

• chr16-19583771-G-A
• rs226849
• NM_020314.7:c.639+2118G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020314.7(VPS35L):​c.639+2118G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 151,726 control chromosomes in the GnomAD database, including 26,174 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.55 (26174 hom., cov: 30)
• Consequence: VPS35L NM_020314.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.435
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.848 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35L	NM_020314.7	MANE Select	c.639+2118G>A		intron	N/A	NP_064710.5
	VPS35L	NM_001365293.2		c.639+2118G>A		intron	N/A	NP_001352222.1
	VPS35L	NM_001365294.2		c.639+2118G>A		intron	N/A	NP_001352223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35L	ENST00000417362.7	TSL:1 MANE Select	c.639+2118G>A		intron	N/A	ENSP00000395973.3
	VPS35L	ENST00000251143.9	TSL:1	c.906+2118G>A		intron	N/A	ENSP00000251143.6
	VPS35L	ENST00000543152.5	TSL:1	c.-30+2118G>A		intron	N/A	ENSP00000457973.1

Frequencies

GnomAD3 genomes AF: 0.549 AC: 83239 AN: 151606 Hom.: 26119 Cov.: 30

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.528

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.549 AC: 83350 AN: 151726 Hom.: 26174 Cov.: 30 AF XY: 0.547 AC XY: 40560 AN XY: 74110

African (AFR) AF: 0.856 AC: 35462 AN: 41450

American (AMR) AF: 0.580 AC: 8850 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1444 AN: 3466

East Asian (EAS) AF: 0.739 AC: 3813 AN: 5160

South Asian (SAS) AF: 0.383 AC: 1837 AN: 4802

European-Finnish (FIN) AF: 0.351 AC: 3647 AN: 10382

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26755 AN: 67890

Other (OTH) AF: 0.530 AC: 1117 AN: 2106

Alfa AF: 0.513 Hom.: 3641

Bravo AF: 0.585

Asia WGS AF: 0.554 AC: 1928 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.4
DANN	Benign	0.15
PhyloP100		-0.43
Mutation Taster		=100/0	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: rs226849; hg19: chr16-19595093;