rs2229515

Positions:

• chr15-29726423-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001330239.4(TJP1):​c.2368A>G​(p.Ile790Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,616 control chromosomes in the GnomAD database, including 12,047 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.11 (970 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11077 hom.)
• Consequence: TJP1 NM_001330239.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.82

Genes affected

TJP1 (HGNC:11827): (tight junction protein 1) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, and acts as a tight junction adaptor protein that also regulates adherens junctions. Tight junctions regulate the movement of ions and macromolecules between endothelial and epithelial cells. The multidomain structure of this scaffold protein, including a postsynaptic density 95/disc-large/zona occludens (PDZ) domain, a Src homology (SH3) domain, a guanylate kinase (GuK) domain and unique (U) motifs all help to co-ordinate binding of transmembrane proteins, cytosolic proteins, and F-actin, which are required for tight junction function. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015475452).
• BP6: Variant 15-29726423-T-C is Benign according to our data. Variant chr15-29726423-T-C is described in ClinVar as [Benign]. Clinvar id is 3056098.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP1	NM_001330239.4	c.2368A>G	p.Ile790Val	missense_variant	18/28	ENST00000614355.5	NP_001317168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP1	ENST00000614355.5	c.2368A>G	p.Ile790Val	missense_variant	18/28	5	NM_001330239.4	ENSP00000483470.2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16355 AN: 152150 Hom.: 970 Cov.: 33

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.0939

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.133 AC: 33109 AN: 249330 Hom.: 2586 AF XY: 0.137 AC XY: 18494 AN XY: 135272

Gnomad AFR exome AF: 0.0697

Gnomad AMR exome AF: 0.167

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.0984

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.117 AC: 170403 AN: 1461348 Hom.: 11077 Cov.: 32 AF XY: 0.120 AC XY: 87360 AN XY: 726996

Gnomad4 AFR exome AF: 0.0709

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.131

Gnomad4 EAS exome AF: 0.0876

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.0994

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.126

GnomAD4 genome AF: 0.107 AC: 16351 AN: 152268 Hom.: 970 Cov.: 33 AF XY: 0.108 AC XY: 8065 AN XY: 74442

Gnomad4 AFR AF: 0.0713

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.126

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.0939

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.135

Alfa AF: 0.115 Hom.: 2077

Bravo AF: 0.107

TwinsUK AF: 0.106 AC: 394

ALSPAC AF: 0.101 AC: 390

ESP6500AA AF: 0.0700 AC: 259

ESP6500EA AF: 0.110 AC: 902

ExAC AF: 0.131 AC: 15842

Asia WGS AF: 0.186 AC: 648 AN: 3478

EpiCase AF: 0.117

EpiControl AF: 0.116

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TJP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;T;.
Eigen	Benign	0.013
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0015	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;.;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.80	N;N;N;.;N
REVEL	Benign	0.068
Sift	Benign	0.096	T;T;T;.;T
Sift4G	Uncertain	0.032	D;D;T;D;D
Polyphen		0.73	P;B;.;.;P
Vest4		0.17
MPC		0.90
ClinPred		0.029	T
GERP RS		3.5
Varity_R		0.14
gMVP		0.30

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229515; hg19: chr15-30018627; COSMIC: COSV62043457; COSMIC: COSV62043457;