chr14-77454101-A-C

Variant names:

• chr14-77454101-A-C
• rs267607172
• NM_001193315.2:c.2T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001193315.2(VIPAS39):​c.2T>G​(p.Met1?) variant causes a start lost, splice region 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VIPAS39 NM_001193315.2 start_lost, splice_region
• Scores: Splicing: ADA: 0.8694
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.86

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-77454101-A-C is Pathogenic according to our data. Variant chr14-77454101-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 115.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr14-77454101-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VIPAS39	NM_001193315.2	c.2T>G	p.Met1?	start_lost, splice_region_variant	Exon 2 of 20	ENST00000557658.6	NP_001180244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VIPAS39	ENST00000557658.6	c.2T>G	p.Met1?	start_lost, splice_region_variant	Exon 2 of 20	1	NM_001193315.2	ENSP00000452191.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Arthrogryposis, renal dysfunction, and cholestasis 2 Pathogenic:1

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.;T;T;.;T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.90	.;D;.;D;.;T;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
PROVEAN	Benign	-1.6	N;N;N;N;N;N;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.
Polyphen		0.98	D;.;D;D;.;.;.
Vest4		0.91
MutPred		0.88		Loss of catalytic residue at M1 (P = 0.0243);Loss of catalytic residue at M1 (P = 0.0243);Loss of catalytic residue at M1 (P = 0.0243);Loss of catalytic residue at M1 (P = 0.0243);Loss of catalytic residue at M1 (P = 0.0243);.;Loss of catalytic residue at M1 (P = 0.0243);
MVP		0.82
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 46

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

Publications

LitVar

Other links and lift over

dbSNP: rs267607172; hg19: chr14-77920444;