14-77428381-G-A

Position:

• chr14-77428381-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001193315.2(VIPAS39):​c.1450C>T​(p.Leu484Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,613,954 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: VIPAS39 NM_001193315.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.43

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056434274).
• BP6: Variant 14-77428381-G-A is Benign according to our data. Variant chr14-77428381-G-A is described in ClinVar as [Benign]. Clinvar id is 791401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77428381-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00183 (278/152290) while in subpopulation EAS AF= 0.0458 (237/5172). AF 95% confidence interval is 0.041. There are 8 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VIPAS39	NM_001193315.2	c.1450C>T	p.Leu484Phe	missense_variant	19/20	ENST00000557658.6	NP_001180244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VIPAS39	ENST00000557658.6	c.1450C>T	p.Leu484Phe	missense_variant	19/20	1	NM_001193315.2	ENSP00000452191	P1

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152172 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0453

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00390 AC: 980 AN: 251192 Hom.: 25 AF XY: 0.00342 AC XY: 464 AN XY: 135768

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0459

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00118 AC: 1729 AN: 1461664 Hom.: 34 Cov.: 32 AF XY: 0.00113 AC XY: 821 AN XY: 727152

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00262

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0355

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152290 Hom.: 8 Cov.: 32 AF XY: 0.00219 AC XY: 163 AN XY: 74470

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0458

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00124 Hom.: 3

Bravo AF: 0.00196

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00338 AC: 411

Asia WGS AF: 0.0140 AC: 47 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.27	T;.;T;T;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;D;.;D
MetaRNN	Benign	0.0056	T;T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.4	M;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	D;.;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0050	D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;.
Vest4		0.85
MVP		0.79
MPC		0.95
ClinPred		0.044	T
GERP RS		5.4
Varity_R		0.37
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs75211061; hg19: chr14-77894724;