chr14-77428465-C-T

Variant names:

• chr14-77428465-C-T
• rs2078466084
• NM_001193315.2:c.1366G>A

Variant summary

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

The NM_001193315.2(VIPAS39):​c.1366G>A​(p.Asp456Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VIPAS39 NM_001193315.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12
• Publications: 0 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.1366G>A	p.Asp456Asn	missense	Exon 19 of 20	NP_001180244.1	Q9H9C1-1
	VIPAS39	NM_001193314.2		c.1366G>A	p.Asp456Asn	missense	Exon 19 of 20	NP_001180243.1	Q9H9C1-1
	VIPAS39	NM_001193317.2		c.1366G>A	p.Asp456Asn	missense	Exon 19 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.1366G>A	p.Asp456Asn	missense	Exon 19 of 20	ENSP00000452191.1	Q9H9C1-1
	VIPAS39	ENST00000343765.6	TSL:1	c.1366G>A	p.Asp456Asn	missense	Exon 20 of 21	ENSP00000339122.2	Q9H9C1-1
	VIPAS39	ENST00000556412.4	TSL:2	c.1444G>A	p.Asp482Asn	missense	Exon 19 of 20	ENSP00000451857.1	G3V4K3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.10
Sift	Benign	0.079	T
Sift4G	Uncertain	0.011	D
Polyphen		0.92	P
Vest4		0.78
MutPred		0.57		Gain of MoRF binding (P = 0.0455)
MVP		0.51
MPC		0.30
ClinPred		0.85	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.36
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2078466084; hg19: chr14-77894808;