NM_001193315.2:c.836+15A>G

Variant names:

• chr14-77437793-T-C
• rs142958086
• NM_001193315.2:c.836+15A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001193315.2(VIPAS39):​c.836+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00849 in 1,612,554 control chromosomes in the GnomAD database, including 160 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (141 hom.)
• Consequence: VIPAS39 NM_001193315.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.577
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• arthrogryposis-renal dysfunction-cholestasis syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-77437793-T-C is Benign according to our data. Variant chr14-77437793-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00876 (1334/152308) while in subpopulation SAS AF = 0.0367 (177/4826). AF 95% confidence interval is 0.0323. There are 19 homozygotes in GnomAd4. There are 631 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.836+15A>G		intron	N/A	NP_001180244.1
	VIPAS39	NM_001193314.2		c.836+15A>G		intron	N/A	NP_001180243.1
	VIPAS39	NM_001193317.2		c.836+15A>G		intron	N/A	NP_001180246.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIPAS39	ENST00000557658.6	TSL:1 MANE Select	c.836+15A>G		intron	N/A	ENSP00000452191.1
	VIPAS39	ENST00000343765.6	TSL:1	c.836+15A>G		intron	N/A	ENSP00000339122.2
	VIPAS39	ENST00000556412.4	TSL:2	c.914+15A>G		intron	N/A	ENSP00000451857.1

Frequencies

GnomAD3 genomes AF: 0.00875 AC: 1331 AN: 152190 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0114 AC: 2867 AN: 251378 AF XY: 0.0132

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.0352

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00711

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.00847 AC: 12362 AN: 1460246 Hom.: 141 Cov.: 31 AF XY: 0.00964 AC XY: 7001 AN XY: 726516

African (AFR) AF: 0.00700 AC: 234 AN: 33442

American (AMR) AF: 0.00543 AC: 243 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 953 AN: 26112

East Asian (EAS) AF: 0.0203 AC: 804 AN: 39672

South Asian (SAS) AF: 0.0377 AC: 3250 AN: 86204

European-Finnish (FIN) AF: 0.00159 AC: 85 AN: 53412

Middle Eastern (MID) AF: 0.0300 AC: 173 AN: 5766

European-Non Finnish (NFE) AF: 0.00528 AC: 5862 AN: 1110578

Other (OTH) AF: 0.0126 AC: 758 AN: 60338

GnomAD4 genome AF: 0.00876 AC: 1334 AN: 152308 Hom.: 19 Cov.: 32 AF XY: 0.00847 AC XY: 631 AN XY: 74482

African (AFR) AF: 0.00741 AC: 308 AN: 41562

American (AMR) AF: 0.00621 AC: 95 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.0148 AC: 77 AN: 5188

South Asian (SAS) AF: 0.0367 AC: 177 AN: 4826

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10620

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68022

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0113 Hom.: 2

Bravo AF: 0.00800

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.78
PhyloP100		-0.58
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs142958086; hg19: chr14-77904136; COSMIC: COSV58938949; COSMIC: COSV58938949;