rs146288421

Variant names:

• chr14-77433829-G-C
• rs146288421
• NM_001193315.2:c.1179+13C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001193315.2(VIPAS39):​c.1179+13C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00853 in 1,613,408 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (141 hom.)
• Consequence: VIPAS39 NM_001193315.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.650
• Publications: 3 publications found

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]

VIPAS39 Gene-Disease associations (from GenCC):

• arthrogryposis, renal dysfunction, and cholestasis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• arthrogryposis-renal dysfunction-cholestasis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 14-77433829-G-C is Benign according to our data. Variant chr14-77433829-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00881 (1341/152280) while in subpopulation SAS AF = 0.0371 (179/4828). AF 95% confidence interval is 0.0326. There are 19 homozygotes in GnomAd4. There are 635 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VIPAS39	NM_001193315.2	c.1179+13C>G		intron_variant	Intron 16 of 19	ENST00000557658.6	NP_001180244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1179+13C>G		intron_variant	Intron 16 of 19	1	NM_001193315.2	ENSP00000452191.1

Frequencies

GnomAD3 genomes AF: 0.00879 AC: 1338 AN: 152162 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00729

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0114 AC: 2866 AN: 251050 AF XY: 0.0132

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.0353

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00712

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.00850 AC: 12419 AN: 1461128 Hom.: 141 Cov.: 32 AF XY: 0.00968 AC XY: 7033 AN XY: 726892

African (AFR) AF: 0.00696 AC: 233 AN: 33460

American (AMR) AF: 0.00544 AC: 243 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 957 AN: 26124

East Asian (EAS) AF: 0.0203 AC: 805 AN: 39674

South Asian (SAS) AF: 0.0378 AC: 3258 AN: 86182

European-Finnish (FIN) AF: 0.00159 AC: 85 AN: 53392

Middle Eastern (MID) AF: 0.0299 AC: 172 AN: 5762

European-Non Finnish (NFE) AF: 0.00531 AC: 5901 AN: 1111480

Other (OTH) AF: 0.0127 AC: 765 AN: 60348

GnomAD4 genome AF: 0.00881 AC: 1341 AN: 152280 Hom.: 19 Cov.: 32 AF XY: 0.00853 AC XY: 635 AN XY: 74466

African (AFR) AF: 0.00741 AC: 308 AN: 41570

American (AMR) AF: 0.00628 AC: 96 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.0148 AC: 77 AN: 5188

South Asian (SAS) AF: 0.0371 AC: 179 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10600

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00729 AC: 496 AN: 68020

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0114 Hom.: 2

Bravo AF: 0.00801

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 10, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.1
DANN	Benign	0.47
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism

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: rs146288421; hg19: chr14-77900172; COSMIC: COSV58938929; COSMIC: COSV58938929;