16-19682271-A-T

Variant names:

• chr16-19682271-A-T
• rs147028064
• NM_020314.7:c.2408A>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_020314.7(VPS35L):​c.2408A>T​(p.Asn803Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000379 in 1,614,018 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (1 hom.)
• Consequence: VPS35L NM_020314.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20
• Publications: 1 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 -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000237 (36/152128) while in subpopulation NFE AF = 0.000412 (28/68036). AF 95% confidence interval is 0.000292. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2408A>T	p.Asn803Ile	missense	Exon 28 of 31	NP_064710.5
	VPS35L	NM_001365293.2		c.2330A>T	p.Asn777Ile	missense	Exon 27 of 30	NP_001352222.1
	VPS35L	NM_001365294.2		c.2207A>T	p.Asn736Ile	missense	Exon 26 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.2408A>T	p.Asn803Ile	missense	Exon 28 of 31	ENSP00000395973.3	Q7Z3J2-1
	VPS35L	ENST00000251143.9	TSL:1	c.2675A>T	p.Asn892Ile	missense	Exon 28 of 31	ENSP00000251143.6	E7EWW0
	VPS35L	ENST00000543152.5	TSL:1	c.1655A>T	p.Asn552Ile	missense	Exon 22 of 25	ENSP00000457973.1	H3BV68

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000302 AC: 76 AN: 251458 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000394 AC: 576 AN: 1461890 Hom.: 1 Cov.: 31 AF XY: 0.000375 AC XY: 273 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000473 AC: 526 AN: 1112010

Other (OTH) AF: 0.000464 AC: 28 AN: 60396

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74326

African (AFR) AF: 0.0000966 AC: 4 AN: 41416

American (AMR) AF: 0.000262 AC: 4 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000454 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000600

EpiControl AF: 0.000533

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	0.25
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.53	T
PhyloP100		6.2
PROVEAN	Pathogenic	-6.2	D
REVEL	Benign	0.27
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.59
MPC		0.75
ClinPred		0.41	T
GERP RS		4.3
gMVP		0.67
Mutation Taster		=36/64	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: rs147028064; hg19: chr16-19693593;