11-134069097-G-A

Position:

• chr11-134069097-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032801.5(JAM3):​c.14G>A​(p.Arg5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: JAM3 NM_032801.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.540

Genes affected

JAM3 (HGNC:15532): (junctional adhesion molecule 3) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. The protein encoded by this immunoglobulin superfamily gene member is localized in the tight junctions between high endothelial cells. Unlike other proteins in this family, the this protein is unable to adhere to leukocyte cell lines and only forms weak homotypic interactions. The encoded protein is a member of the junctional adhesion molecule protein family and acts as a receptor for another member of this family. A mutation in an intron of this gene is associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3204764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
JAM3	NM_032801.5	c.14G>A	p.Arg5Gln	missense_variant	1/9	ENST00000299106.9	NP_116190.3
JAM3	NM_001205329.2	c.14G>A	p.Arg5Gln	missense_variant	1/8		NP_001192258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
JAM3	ENST00000299106.9	c.14G>A	p.Arg5Gln	missense_variant	1/9	1	NM_032801.5	ENSP00000299106	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459280 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726066

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 5 of the JAM3 protein (p.Arg5Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with JAM3-related conditions. ClinVar contains an entry for this variant (Variation ID: 2099545). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T;T;.
Eigen	Benign	-0.098
Eigen_PC	Benign	0.0031
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.32	T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	0.85	D;N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.27
Sift	Uncertain	0.027	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.80	P;.;.
Vest4		0.28
MutPred		0.50		Loss of MoRF binding (P = 0.0135);Loss of MoRF binding (P = 0.0135);Loss of MoRF binding (P = 0.0135);
MVP		0.84
MPC		0.095
ClinPred		0.80	D
GERP RS		4.3
Varity_R		0.13
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-133938992;