chr16-19616152-A-C

Variant names:

• chr16-19616152-A-C
• rs140203828
• NM_020314.7:c.1062A>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_020314.7(VPS35L):​c.1062A>C​(p.Leu354Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,613,634 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (36 hom.)
• Consequence: VPS35L NM_020314.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14
• Publications: 2 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 16-19616152-A-C is Benign according to our data. Variant chr16-19616152-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2646277.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00472 (719/152174) while in subpopulation NFE AF = 0.00719 (489/68002). AF 95% confidence interval is 0.00666. There are 6 homozygotes in GnomAd4. There are 338 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.1062A>C	p.Leu354Leu	synonymous	Exon 13 of 31	NP_064710.5
	VPS35L	NM_001365293.2		c.1062A>C	p.Leu354Leu	synonymous	Exon 13 of 30	NP_001352222.1
	VPS35L	NM_001365295.2		c.174A>C	p.Leu58Leu	synonymous	Exon 14 of 32	NP_001352224.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS35L	ENST00000417362.7	TSL:1 MANE Select	c.1062A>C	p.Leu354Leu	synonymous	Exon 13 of 31	ENSP00000395973.3	Q7Z3J2-1
	VPS35L	ENST00000251143.9	TSL:1	c.1329A>C	p.Leu443Leu	synonymous	Exon 13 of 31	ENSP00000251143.6	E7EWW0
	VPS35L	ENST00000543152.5	TSL:1	c.309A>C	p.Leu103Leu	synonymous	Exon 7 of 25	ENSP00000457973.1	H3BV68

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 722 AN: 152056 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000870

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00720

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00537 AC: 1351 AN: 251452 AF XY: 0.00569

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00379

Gnomad NFE exome AF: 0.00803

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00544 AC: 7946 AN: 1461460 Hom.: 36 Cov.: 30 AF XY: 0.00545 AC XY: 3965 AN XY: 727050

African (AFR) AF: 0.000657 AC: 22 AN: 33468

American (AMR) AF: 0.00371 AC: 166 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00747 AC: 195 AN: 26116

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

South Asian (SAS) AF: 0.00347 AC: 299 AN: 86212

European-Finnish (FIN) AF: 0.00433 AC: 231 AN: 53402

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5762

European-Non Finnish (NFE) AF: 0.00598 AC: 6648 AN: 1111702

Other (OTH) AF: 0.00527 AC: 318 AN: 60382

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152174 Hom.: 6 Cov.: 32 AF XY: 0.00454 AC XY: 338 AN XY: 74408

African (AFR) AF: 0.000867 AC: 36 AN: 41512

American (AMR) AF: 0.00380 AC: 58 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4818

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10596

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00719 AC: 489 AN: 68002

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00664 Hom.: 1

Bravo AF: 0.00473

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00979

EpiControl AF: 0.00824

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.96
DANN	Benign	0.73
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.070		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: rs140203828; hg19: chr16-19627474;