19-17360779-C-G

Variant names:

• chr19-17360779-C-G
• rs370830558
• NM_031310.3:c.1233G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031310.3(PLVAP):​c.1233G>C​(p.Gln411His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 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. Q411P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 31)
  • Failed GnomAD Quality Control
• Consequence: PLVAP NM_031310.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.22
• Publications: 0 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

ENSG00000269350 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12482521).

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.1233G>C	p.Gln411His	missense	Exon 4 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.1233G>C	p.Gln411His	missense	Exon 4 of 6	ENSP00000252590.3	Q9BX97
	PLVAP	ENST00000962152.1		c.1233G>C	p.Gln411His	missense	Exon 4 of 7	ENSP00000632211.1
	PLVAP	ENST00000962153.1		c.1227G>C	p.Gln409His	missense	Exon 4 of 6	ENSP00000632212.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152156 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152156 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.15
DANN	Benign	0.97
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		-2.2
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.038
Sift	Benign	0.14	T
Sift4G	Benign	0.15	T
Polyphen		0.60	P
Vest4		0.22
MutPred		0.45		Loss of stability (P = 0.3654)
MVP		0.088
MPC		0.69
ClinPred		0.28	T
GERP RS		-3.1
Varity_R		0.054
gMVP		0.21
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs370830558; hg19: chr19-17471588;