14-77427630-G-T

Variant names:

• chr14-77427630-G-T
• rs777254676
• NM_001193315.2:c.1468C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001193315.2(VIPAS39):​c.1468C>A​(p.Arg490Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000342 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: VIPAS39 NM_001193315.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75
• Publications: 4 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• arthrogryposis-renal dysfunction-cholestasis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIPAS39	NM_001193315.2	MANE Select	c.1468C>A	p.Arg490Arg	synonymous	Exon 20 of 20	NP_001180244.1	Q9H9C1-1
	VIPAS39	NM_001193314.2		c.1468C>A	p.Arg490Arg	synonymous	Exon 20 of 20	NP_001180243.1	Q9H9C1-1
	VIPAS39	NM_001193317.2		c.1468C>A	p.Arg490Arg	synonymous	Exon 20 of 20	NP_001180246.1	Q9H9C1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIPAS39	ENST00000557658.6	TSL:1 MANE Select	c.1468C>A	p.Arg490Arg	synonymous	Exon 20 of 20	ENSP00000452191.1	Q9H9C1-1
	VIPAS39	ENST00000343765.6	TSL:1	c.1468C>A	p.Arg490Arg	synonymous	Exon 21 of 21	ENSP00000339122.2	Q9H9C1-1
	VIPAS39	ENST00000556412.4	TSL:2	c.1546C>A	p.Arg516Arg	synonymous	Exon 20 of 20	ENSP00000451857.1	G3V4K3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251438 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461858 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.79
PhyloP100		6.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs777254676; hg19: chr14-77893973;