rs267607171

Variant names:

• chr14-77435885-G-A
• rs267607171
• NM_001193315.2:c.871C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001193315.2(VIPAS39):​c.871C>T​(p.Gln291*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VIPAS39 NM_001193315.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.66
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-77435885-G-A is Pathogenic according to our data. Variant chr14-77435885-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 114.Status of the report is no_assertion_criteria_provided, 0 stars.

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.871C>T	p.Gln291*	stop_gained	Exon 13 of 20	NP_001180244.1	Q9H9C1-1
	VIPAS39	NM_001193314.2		c.871C>T	p.Gln291*	stop_gained	Exon 13 of 20	NP_001180243.1	Q9H9C1-1
	VIPAS39	NM_001193317.2		c.871C>T	p.Gln291*	stop_gained	Exon 13 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.871C>T	p.Gln291*	stop_gained	Exon 13 of 20	ENSP00000452191.1	Q9H9C1-1
	VIPAS39	ENST00000343765.6	TSL:1	c.871C>T	p.Gln291*	stop_gained	Exon 14 of 21	ENSP00000339122.2	Q9H9C1-1
	VIPAS39	ENST00000556412.4	TSL:2	c.949C>T	p.Gln317*	stop_gained	Exon 13 of 20	ENSP00000451857.1	G3V4K3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Arthrogryposis, renal dysfunction, and cholestasis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		7.7
Vest4		0.44
GERP RS		4.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: 34

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

Other links and lift over

dbSNP: rs267607171; hg19: chr14-77902228;