chr14-77428509-C-G

Variant names:

• chr14-77428509-C-G
• rs113067724
• NM_001193315.2:c.1357-35G>C

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.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 (★★). There are indicators that this mutation may affect the branch point..

• 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:3
• Conservation: PhyloP100: 0.0310
• Publications: 1 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: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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 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.1357-35G>C		intron_variant	Intron 18 of 19	ENST00000557658.6	NP_001180244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1357-35G>C		intron_variant	Intron 18 of 19	1	NM_001193315.2	ENSP00000452191.1

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

GnomAD2 exomes AF: 0.0153 AC: 3775 AN: 246980 AF XY: 0.0156

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 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

African (AFR) AF: 0.00286 AC: 95 AN: 33212

American (AMR) AF: 0.0110 AC: 489 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 412 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00393 AC: 337 AN: 85780

European-Finnish (FIN) AF: 0.0201 AC: 1051 AN: 52382

Middle Eastern (MID) AF: 0.0115 AC: 66 AN: 5746

European-Non Finnish (NFE) AF: 0.0222 AC: 24466 AN: 1099702

Other (OTH) AF: 0.0178 AC: 1068 AN: 59866

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

African (AFR) AF: 0.00399 AC: 166 AN: 41556

American (AMR) AF: 0.0169 AC: 258 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4824

European-Finnish (FIN) AF: 0.0218 AC: 231 AN: 10604

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1459 AN: 68016

Other (OTH) AF: 0.0161 AC: 34 AN: 2108

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 23, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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	-0.86
CADD	Benign	1.4
DANN	Benign	0.78
PhyloP100		0.031
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs113067724; hg19: chr14-77894852;