rs17105786

Variant names:

• chr14-77428231-T-C
• rs17105786
• NM_001193315.2:c.1461+139A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001193315.2(VIPAS39):​c.1461+139A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 759,232 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (16 hom.)
• Consequence: VIPAS39 NM_001193315.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.826
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 14-77428231-T-C is Benign according to our data. Variant chr14-77428231-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1202490.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1882/152280) while in subpopulation AFR AF = 0.0428 (1778/41560). AF 95% confidence interval is 0.0411. There are 39 homozygotes in GnomAd4. There are 897 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

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.1461+139A>G		intron	N/A	NP_001180244.1	Q9H9C1-1
	VIPAS39	NM_001193314.2		c.1461+139A>G		intron	N/A	NP_001180243.1	Q9H9C1-1
	VIPAS39	NM_001193317.2		c.1461+139A>G		intron	N/A	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.1461+139A>G		intron	N/A	ENSP00000452191.1	Q9H9C1-1
	VIPAS39	ENST00000343765.6	TSL:1	c.1461+139A>G		intron	N/A	ENSP00000339122.2	Q9H9C1-1
	VIPAS39	ENST00000556412.4	TSL:2	c.1539+139A>G		intron	N/A	ENSP00000451857.1	G3V4K3

Frequencies

GnomAD3 genomes AF: 0.0123 AC: 1870 AN: 152162 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0426

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0119

GnomAD4 exome AF: 0.00167 AC: 1012 AN: 606952 Hom.: 16 AF XY: 0.00141 AC XY: 459 AN XY: 325002

African (AFR) AF: 0.0418 AC: 699 AN: 16718

American (AMR) AF: 0.00235 AC: 81 AN: 34414

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 70 AN: 20060

East Asian (EAS) AF: 0.00 AC: 0 AN: 31536

South Asian (SAS) AF: 0.000158 AC: 10 AN: 63184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34648

Middle Eastern (MID) AF: 0.00314 AC: 8 AN: 2548

European-Non Finnish (NFE) AF: 0.000118 AC: 44 AN: 371862

Other (OTH) AF: 0.00313 AC: 100 AN: 31982

GnomAD4 genome AF: 0.0124 AC: 1882 AN: 152280 Hom.: 39 Cov.: 32 AF XY: 0.0120 AC XY: 897 AN XY: 74470

African (AFR) AF: 0.0428 AC: 1778 AN: 41560

American (AMR) AF: 0.00373 AC: 57 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0118 Hom.: 4

Bravo AF: 0.0137

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.47
PhyloP100		-0.83
Mutation Taster		=100/0	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: rs17105786; hg19: chr14-77894574;