14-77428509-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001193315.2(VIPAS39):c.1357-35G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,599,034 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (19 hom., cov: 32)
  • Exomes 𝑓: 0.019 (297 hom.)
• Consequence: VIPAS39 NM_001193315.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0310

Genes affected

VIPAS39 (HGNC:20347): (VPS33B interacting protein, apical-basolateral polarity regulator, spe-39 homolog) Involved in endosome to lysosome transport and intracellular protein transport. Acts upstream of or within collagen metabolic process and peptidyl-lysine hydroxylation. Located in Golgi apparatus and endosome. Implicated in arthrogryposis, renal dysfunction, and cholestasis 2. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-77428509-C-G is Benign according to our data. Variant chr14-77428509-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 261488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2288/152266) while in subpopulation NFE AF= 0.0215 (1459/68016). AF 95% confidence interval is 0.0205. There are 19 homozygotes in gnomad4. There are 1100 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIPAS39	NM_001193315.2	c.1357-35G>C		intron_variant		ENST00000557658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1357-35G>C		intron_variant		1	NM_001193315.2	P1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2289 AN: 152148 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0153 AC: 3775 AN: 246980 Hom.: 41 AF XY: 0.0156 AC XY: 2081 AN XY: 133582

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00395

Gnomad FIN exome AF: 0.0217

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.0193 AC: 27984 AN: 1446768 Hom.: 297 Cov.: 27 AF XY: 0.0192 AC XY: 13825 AN XY: 720646

Gnomad4 AFR exome AF: 0.00286

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00393

Gnomad4 FIN exome AF: 0.0201

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0150 AC: 2288 AN: 152266 Hom.: 19 Cov.: 32 AF XY: 0.0148 AC XY: 1100 AN XY: 74440

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00866 Hom.: 2

Bravo AF: 0.0144

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 23, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.4
Dann	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs113067724; hg19: chr14-77894852;