chr19-17360784-G-A

Variant names:

• chr19-17360784-G-A
• rs769449142
• NM_031310.3:c.1228C>T

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.1228C>T​(p.Pro410Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P410T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PLVAP NM_031310.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• 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=0.26017332).

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.1228C>T	p.Pro410Ser	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.1228C>T	p.Pro410Ser	missense	Exon 4 of 6	ENSP00000252590.3	Q9BX97
	PLVAP	ENST00000962152.1		c.1228C>T	p.Pro410Ser	missense	Exon 4 of 7	ENSP00000632211.1
	PLVAP	ENST00000962153.1		c.1222C>T	p.Pro408Ser	missense	Exon 4 of 6	ENSP00000632212.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251422 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461544 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111692

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.0
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.13
Sift	Benign	0.053	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.27
MutPred		0.60		Gain of phosphorylation at P410 (P = 0.0269)
MVP		0.29
MPC		0.89
ClinPred		0.92	D
GERP RS		2.5
Varity_R		0.043
gMVP		0.24
Mutation Taster		=97/3	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: rs769449142; hg19: chr19-17471593; COSMIC: COSV108049970; COSMIC: COSV108049970;