rs397515439

chr11-134144330-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_032801.5(JAM3):c.346G>A(p.Glu116Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: JAM3 NM_032801.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.56

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774
• PP5: Variant 11-134144330-G-A is Pathogenic according to our data. Variant chr11-134144330-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 41882.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-134144330-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAM3	NM_032801.5	c.346G>A	p.Glu116Lys	missense_variant	4/9	ENST00000299106.9
JAM3	NM_001205329.2	c.257-462G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAM3	ENST00000299106.9	c.346G>A	p.Glu116Lys	missense_variant	4/9	1	NM_032801.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Porencephaly-microcephaly-bilateral congenital cataract syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Pathology and Clinical Laboratory Medicine, King Fahad Medical City	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.60		Gain of MoRF binding (P = 0.0024);.;
MVP		0.80
MPC		0.49
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397515439; hg19: chr11-134014225;