14-77428376-G-T

Variant names:

• chr14-77428376-G-T
• rs145453157
• NM_001193315.2:c.1455C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001193315.2(VIPAS39):​c.1455C>A​(p.Ser485Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,746 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (10 hom.)
• Consequence: VIPAS39 NM_001193315.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.31
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022336543).
• BP6: Variant 14-77428376-G-T is Benign according to our data. Variant chr14-77428376-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 498683.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0014 (213/152266) while in subpopulation NFE AF = 0.00254 (173/68016). AF 95% confidence interval is 0.00223. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193315.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIPAS39	NM_001193315.2	MANE Select	c.1455C>A	p.Ser485Arg	missense	Exon 19 of 20	NP_001180244.1
	VIPAS39	NM_001193314.2		c.1455C>A	p.Ser485Arg	missense	Exon 19 of 20	NP_001180243.1
	VIPAS39	NM_001193317.2		c.1455C>A	p.Ser485Arg	missense	Exon 19 of 20	NP_001180246.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIPAS39	ENST00000557658.6	TSL:1 MANE Select	c.1455C>A	p.Ser485Arg	missense	Exon 19 of 20	ENSP00000452191.1
	VIPAS39	ENST00000343765.6	TSL:1	c.1455C>A	p.Ser485Arg	missense	Exon 20 of 21	ENSP00000339122.2
	VIPAS39	ENST00000556412.4	TSL:2	c.1533C>A	p.Ser511Arg	missense	Exon 19 of 20	ENSP00000451857.1

Frequencies

GnomAD3 genomes AF: 0.00140 AC: 213 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00129 AC: 324 AN: 251124 AF XY: 0.00130

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000371

Gnomad NFE exome AF: 0.00255

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00220 AC: 3212 AN: 1461480 Hom.: 10 Cov.: 32 AF XY: 0.00214 AC XY: 1556 AN XY: 727088

African (AFR) AF: 0.000359 AC: 12 AN: 33466

American (AMR) AF: 0.000246 AC: 11 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86236

European-Finnish (FIN) AF: 0.000375 AC: 20 AN: 53310

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00274 AC: 3049 AN: 1111794

Other (OTH) AF: 0.00186 AC: 112 AN: 60372

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74460

African (AFR) AF: 0.000529 AC: 22 AN: 41558

American (AMR) AF: 0.000654 AC: 10 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00184 Hom.: 1

Bravo AF: 0.00133

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00140 AC: 170

EpiCase AF: 0.00213

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Feb 09, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VIPAS39: BP4

Arthrogryposis, renal dysfunction, and cholestasis 2 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jul 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VIPAS39 c.1455C>A (p.Ser485Arg) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0013 in 251124 control chromosomes, predominantly at a frequency of 0.0026 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in VIPAS39 causing Arthrogryposis, Renal Dysfunction, And Cholestasis 2 phenotype. To our knowledge, no occurrence of c.1455C>A in individuals affected with Arthrogryposis, Renal Dysfunction, And Cholestasis 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 498683). Based on the evidence outlined above, the variant was classified as likely benign.

VIPAS39-related disorder Benign:1

Feb 07, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.087
Sift	Benign	0.67	T
Sift4G	Uncertain	0.019	D
Polyphen		0.0030	B
Vest4		0.51
MutPred		0.48		Gain of MoRF binding (P = 0.0166)
MVP		0.29
MPC		0.29
ClinPred		0.0041	T
GERP RS		1.4
Varity_R		0.026
gMVP		0.076
Mutation Taster		=99/1	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: rs145453157; hg19: chr14-77894719;