rs2291166

Positions:

• chr15-29716773-T-G

Variant summary

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

The NM_001330239.4(TJP1):​c.4040A>C​(p.Asp1347Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,614,036 control chromosomes in the GnomAD database, including 2,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.044 (167 hom., cov: 33)
  • Exomes 𝑓: 0.059 (2786 hom.)
• Consequence: TJP1 NM_001330239.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.67

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=0.0036012828).
• BP6: Variant 15-29716773-T-G is Benign according to our data. Variant chr15-29716773-T-G is described in ClinVar as [Benign]. Clinvar id is 3056593.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TJP1	NM_001330239.4	c.4040A>C	p.Asp1347Ala	missense_variant	23/28	ENST00000614355.5	NP_001317168.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TJP1	ENST00000614355.5	c.4040A>C	p.Asp1347Ala	missense_variant	23/28	5	NM_001330239.4	ENSP00000483470.2

Frequencies

GnomAD3 genomes AF: 0.0444 AC: 6754 AN: 152154 Hom.: 167 Cov.: 33

Gnomad AFR AF: 0.0238

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0544

Gnomad EAS AF: 0.0329

Gnomad SAS AF: 0.0777

Gnomad FIN AF: 0.0528

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0587

Gnomad OTH AF: 0.0430

GnomAD3 exomes AF: 0.0494 AC: 12333 AN: 249524 Hom.: 403 AF XY: 0.0528 AC XY: 7151 AN XY: 135384

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0518

Gnomad EAS exome AF: 0.0343

Gnomad SAS exome AF: 0.0862

Gnomad FIN exome AF: 0.0499

Gnomad NFE exome AF: 0.0545

Gnomad OTH exome AF: 0.0492

GnomAD4 exome AF: 0.0585 AC: 85583 AN: 1461764 Hom.: 2786 Cov.: 35 AF XY: 0.0595 AC XY: 43282 AN XY: 727158

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.0205

Gnomad4 ASJ exome AF: 0.0554

Gnomad4 EAS exome AF: 0.0277

Gnomad4 SAS exome AF: 0.0835

Gnomad4 FIN exome AF: 0.0505

Gnomad4 NFE exome AF: 0.0609

Gnomad4 OTH exome AF: 0.0578

GnomAD4 genome AF: 0.0444 AC: 6756 AN: 152272 Hom.: 167 Cov.: 33 AF XY: 0.0437 AC XY: 3253 AN XY: 74454

Gnomad4 AFR AF: 0.0239

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.0544

Gnomad4 EAS AF: 0.0328

Gnomad4 SAS AF: 0.0774

Gnomad4 FIN AF: 0.0528

Gnomad4 NFE AF: 0.0588

Gnomad4 OTH AF: 0.0425

Alfa AF: 0.0536 Hom.: 585

Bravo AF: 0.0401

TwinsUK AF: 0.0626 AC: 232

ALSPAC AF: 0.0695 AC: 268

ESP6500AA AF: 0.0273 AC: 102

ESP6500EA AF: 0.0572 AC: 470

ExAC AF: 0.0490 AC: 5921

Asia WGS AF: 0.0550 AC: 195 AN: 3478

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

Jul 13, 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;T;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.8	L;.;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;N;D;.;N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Benign	0.088	T;D;T;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.75
MPC		0.44
ClinPred		0.021	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.49

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: rs2291166; hg19: chr15-30008977; COSMIC: COSV62046438; COSMIC: COSV62046438;