chr19-17365393-G-C

Variant names:

• chr19-17365393-G-C
• rs761158492
• NM_031310.3:c.1072C>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS1

The NM_031310.3(PLVAP):​c.1072C>G​(p.Arg358Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R358L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PLVAP NM_031310.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0750
• Publications: 5 publications found

Genes affected

PLVAP (HGNC:13635): (plasmalemma vesicle associated protein) Predicted to enable identical protein binding activity. Involved in MAPK cascade; positive regulation of cellular extravasation; and tumor necrosis factor-mediated signaling pathway. Located in cell surface. Colocalizes with caveola. Implicated in congenital diarrhea. [provided by Alliance of Genome Resources, Apr 2022]

PLVAP Gene-Disease associations (from GenCC):

• diarrhea 10, protein-losing enteropathy type

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital diarrhea 7 with exudative enteropathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31024957).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000411 (6/1461002) while in subpopulation EAS AF = 0.000151 (6/39700). AF 95% confidence interval is 0.0000651. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031310.3. 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
	PLVAP	NM_031310.3	MANE Select	c.1072C>G	p.Arg358Gly	missense	Exon 3 of 6	NP_112600.1	Q9BX97

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLVAP	ENST00000252590.9	TSL:1 MANE Select	c.1072C>G	p.Arg358Gly	missense	Exon 3 of 6	ENSP00000252590.3	Q9BX97
	PLVAP	ENST00000962152.1		c.1072C>G	p.Arg358Gly	missense	Exon 3 of 7	ENSP00000632211.1
	PLVAP	ENST00000962153.1		c.1072C>G	p.Arg358Gly	missense	Exon 3 of 6	ENSP00000632212.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250766 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461002 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726882

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.075
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.12
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.023	D
Polyphen		0.99	D
Vest4		0.35
MutPred		0.47		Loss of MoRF binding (P = 0.0342)
MVP		0.23
MPC		1.0
ClinPred		0.69	D
GERP RS		1.7
Varity_R		0.31
gMVP		0.39
Mutation Taster		=93/7	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: rs761158492; hg19: chr19-17476202;