rs76396354

Variant names:

• chr14-77441138-T-C
• rs76396354
• NM_001193315.2:c.735-45A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001193315.2(VIPAS39):​c.735-45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 1,611,160 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (213 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (199 hom.)
• Consequence: VIPAS39 NM_001193315.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.144
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 14-77441138-T-C is Benign according to our data. Variant chr14-77441138-T-C is described in ClinVar as Benign. ClinVar VariationId is 261491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0998 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIPAS39	NM_001193315.2	MANE Select	c.735-45A>G		intron	N/A	NP_001180244.1
	VIPAS39	NM_001193314.2		c.735-45A>G		intron	N/A	NP_001180243.1
	VIPAS39	NM_001193317.2		c.735-45A>G		intron	N/A	NP_001180246.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIPAS39	ENST00000557658.6	TSL:1 MANE Select	c.735-45A>G		intron	N/A	ENSP00000452191.1
	VIPAS39	ENST00000343765.6	TSL:1	c.735-45A>G		intron	N/A	ENSP00000339122.2
	VIPAS39	ENST00000553691.5	TSL:5	n.660A>G		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4486 AN: 152142 Hom.: 213 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00767 AC: 1929 AN: 251402 AF XY: 0.00550

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00512

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00296 AC: 4325 AN: 1458900 Hom.: 199 Cov.: 30 AF XY: 0.00255 AC XY: 1849 AN XY: 725860

African (AFR) AF: 0.104 AC: 3457 AN: 33386

American (AMR) AF: 0.00533 AC: 238 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00125 AC: 108 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5754

European-Non Finnish (NFE) AF: 0.000114 AC: 126 AN: 1109882

Other (OTH) AF: 0.00616 AC: 371 AN: 60190

GnomAD4 genome AF: 0.0295 AC: 4492 AN: 152260 Hom.: 213 Cov.: 33 AF XY: 0.0288 AC XY: 2145 AN XY: 74466

African (AFR) AF: 0.102 AC: 4246 AN: 41482

American (AMR) AF: 0.0115 AC: 176 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68036

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0144 Hom.: 38

Bravo AF: 0.0336

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs76396354; hg19: chr14-77907481;