16-19573123-G-A

Variant names:

• chr16-19573123-G-A
• rs139739334
• NM_020314.7:c.290G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_020314.7(VPS35L):​c.290G>A​(p.Ser97Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000306 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: VPS35L NM_020314.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 5 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.022).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000316 (461/1461164) while in subpopulation AMR AF = 0.000739 (33/44658). AF 95% confidence interval is 0.00054. There are 0 homozygotes in GnomAdExome4. There are 208 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.290G>A	p.Ser97Asn	missense	Exon 4 of 31	NP_064710.5
	VPS35L	NM_001365293.2		c.290G>A	p.Ser97Asn	missense	Exon 4 of 30	NP_001352222.1
	VPS35L	NM_001365294.2		c.290G>A	p.Ser97Asn	missense	Exon 4 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.290G>A	p.Ser97Asn	missense	Exon 4 of 31	ENSP00000395973.3	Q7Z3J2-1
	VPS35L	ENST00000251143.9	TSL:1	c.557G>A	p.Ser186Asn	missense	Exon 4 of 31	ENSP00000251143.6	E7EWW0
	VPS35L	ENST00000513947.8	TSL:1	c.290G>A	p.Ser97Asn	missense	Exon 4 of 14	ENSP00000458116.3	H3BVG8

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251224 AF XY: 0.000258

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000316 AC: 461 AN: 1461164 Hom.: 0 Cov.: 30 AF XY: 0.000286 AC XY: 208 AN XY: 726888

African (AFR) AF: 0.0000598 AC: 2 AN: 33462

American (AMR) AF: 0.000739 AC: 33 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000363 AC: 403 AN: 1111596

Other (OTH) AF: 0.000381 AC: 23 AN: 60346

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74322

African (AFR) AF: 0.0000483 AC: 2 AN: 41420

American (AMR) AF: 0.000524 AC: 8 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68036

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000314 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000109

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.012	T
PhyloP100		1.9
ClinPred		0.034	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139739334; hg19: chr16-19584445; COSMIC: COSV105083280; COSMIC: COSV105083280;