16-19573212-C-T

Variant names:

• chr16-19573212-C-T
• rs199767367
• NM_020314.7:c.379C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001365295.2(VPS35L):​c.-581C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: VPS35L NM_001365295.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365295.2. 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.379C>T	p.Arg127Trp	missense	Exon 4 of 31	NP_064710.5
	VPS35L	NM_001365295.2		c.-581C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 32	NP_001352224.1
	VPS35L	NM_001365293.2		c.379C>T	p.Arg127Trp	missense	Exon 4 of 30	NP_001352222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35L	ENST00000417362.7	TSL:1 MANE Select	c.379C>T	p.Arg127Trp	missense	Exon 4 of 31	ENSP00000395973.3	Q7Z3J2-1
	VPS35L	ENST00000251143.9	TSL:1	c.646C>T	p.Arg216Trp	missense	Exon 4 of 31	ENSP00000251143.6	E7EWW0
	VPS35L	ENST00000513947.8	TSL:1	c.379C>T	p.Arg127Trp	missense	Exon 4 of 14	ENSP00000458116.3	H3BVG8

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251472 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461664 Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000358 AC: 16 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111852

Other (OTH) AF: 0.000116 AC: 7 AN: 60382

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000581 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.47	T
PhyloP100		3.5
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.57
MPC		0.85
ClinPred		0.73	D
GERP RS		4.3
gMVP		0.61
Mutation Taster		=17/83	disease causing

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: rs199767367; hg19: chr16-19584534;