14-77428376-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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. 16/21 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:3
• Conservation: PhyloP100: 1.31

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 -9 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 id is 498683.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VIPAS39	NM_001193315.2	c.1455C>A	p.Ser485Arg	missense_variant	19/20	ENST00000557658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1455C>A	p.Ser485Arg	missense_variant	19/20	1	NM_001193315.2	P1

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

GnomAD3 exomes AF: 0.00129 AC: 324 AN: 251124 Hom.: 1 AF XY: 0.00130 AC XY: 177 AN XY: 135730

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 SAS 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

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00274

Gnomad4 OTH exome AF: 0.00186

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

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00254

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00195 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:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	VIPAS39: BP4 -

Arthrogryposis, renal dysfunction, and cholestasis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

VIPAS39-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2022

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 v4.3

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;.;T;T;.;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.022	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	L;.;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.50	N;.;N;N;N;N
REVEL	Benign	0.087
Sift	Benign	0.67	T;.;T;T;T;T
Sift4G	Uncertain	0.019	D;D;D;D;D;D
Polyphen		0.0030	B;.;B;B;.;.
Vest4		0.51
MutPred		0.48		Gain of MoRF binding (P = 0.0166);.;Gain of MoRF binding (P = 0.0166);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

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: rs145453157; hg19: chr14-77894719;