rs148698913

Variant names:

• chr14-77435895-G-A
• rs148698913
• NM_001193315.2:c.861C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001193315.2(VIPAS39):​c.861C>T​(p.Ser287Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00502 in 1,614,080 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (110 hom.)
• Consequence: VIPAS39 NM_001193315.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.360
• Publications: 5 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 14-77435895-G-A is Benign according to our data. Variant chr14-77435895-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00418 (637/152248) while in subpopulation SAS AF = 0.0342 (165/4818). AF 95% confidence interval is 0.03. There are 13 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.861C>T	p.Ser287Ser	synonymous	Exon 13 of 20	NP_001180244.1	Q9H9C1-1
	VIPAS39	NM_001193314.2		c.861C>T	p.Ser287Ser	synonymous	Exon 13 of 20	NP_001180243.1	Q9H9C1-1
	VIPAS39	NM_001193317.2		c.861C>T	p.Ser287Ser	synonymous	Exon 13 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.861C>T	p.Ser287Ser	synonymous	Exon 13 of 20	ENSP00000452191.1	Q9H9C1-1
	VIPAS39	ENST00000343765.6	TSL:1	c.861C>T	p.Ser287Ser	synonymous	Exon 14 of 21	ENSP00000339122.2	Q9H9C1-1
	VIPAS39	ENST00000556412.4	TSL:2	c.939C>T	p.Ser313Ser	synonymous	Exon 13 of 20	ENSP00000451857.1	G3V4K3

Frequencies

GnomAD3 genomes AF: 0.00420 AC: 639 AN: 152130 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00806 AC: 2026 AN: 251378 AF XY: 0.00972

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.0330

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00510 AC: 7462 AN: 1461832 Hom.: 110 Cov.: 31 AF XY: 0.00620 AC XY: 4507 AN XY: 727228

African (AFR) AF: 0.000627 AC: 21 AN: 33474

American (AMR) AF: 0.00165 AC: 74 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 900 AN: 26132

East Asian (EAS) AF: 0.0203 AC: 806 AN: 39694

South Asian (SAS) AF: 0.0352 AC: 3040 AN: 86258

European-Finnish (FIN) AF: 0.00103 AC: 55 AN: 53414

Middle Eastern (MID) AF: 0.0220 AC: 127 AN: 5766

European-Non Finnish (NFE) AF: 0.00175 AC: 1950 AN: 1111984

Other (OTH) AF: 0.00810 AC: 489 AN: 60392

GnomAD4 genome AF: 0.00418 AC: 637 AN: 152248 Hom.: 13 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74444

African (AFR) AF: 0.000578 AC: 24 AN: 41556

American (AMR) AF: 0.00157 AC: 24 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3472

East Asian (EAS) AF: 0.0147 AC: 76 AN: 5176

South Asian (SAS) AF: 0.0342 AC: 165 AN: 4818

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00272 AC: 185 AN: 68014

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00430 Hom.: 2

Bravo AF: 0.00325

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.00376

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs148698913; hg19: chr14-77902238; COSMIC: COSV58938941; COSMIC: COSV58938941;