14-77428371-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001193315.2(VIPAS39):c.1460C>T(p.Ser487Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S487S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: VIPAS39 NM_001193315.2 missense, splice_region
• Scores: Splicing: ADA: 0.06385
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.668

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010129333).
• BP6: Variant 14-77428371-G-A is Benign according to our data. Variant chr14-77428371-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 501089.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000749 (114/152254) while in subpopulation AFR AF= 0.00255 (106/41544). AF 95% confidence interval is 0.00216. There are 0 homozygotes in gnomad4. There are 49 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.1460C>T	p.Ser487Leu	missense_variant, splice_region_variant	19/20	ENST00000557658.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1460C>T	p.Ser487Leu	missense_variant, splice_region_variant	19/20	1	NM_001193315.2	P1

Frequencies

GnomAD3 genomes AF: 0.000743 AC: 113 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251004 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135676

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461278 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 726986

Gnomad4 AFR exome AF: 0.00215

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74446

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.000763

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000255 AC: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 20, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 21, 2023

Variant summary: VIPAS39 c.1460C>T (p.Ser487Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00021 in 251004 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1460C>T in individuals affected with Arthrogryposis, Renal Dysfunction, And Cholestasis 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

VIPAS39-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 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	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.;T;T;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	-0.14	N;.;N;N;.;.
MutationTaster	Benign	0.55	D;D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.58	N;.;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.14	T;.;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T
Polyphen		0.0050	B;.;B;B;.;.
Vest4		0.26
MVP		0.49
MPC		0.23
ClinPred		0.024	T
GERP RS		3.6
Varity_R		0.037
gMVP		0.071

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.064
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.010		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: rs140365206; hg19: chr14-77894714;