rs397514678

chr11-134069085-T-Achr11-134069085-T-Cchr11-134069085-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_032801.5(JAM3):c.2T>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: JAM3 NM_032801.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.37

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_032801.5 (JAM3) was described as [Pathogenic] in ClinVar as 41883
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-134069085-T-A is Pathogenic according to our data. Variant chr11-134069085-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 931312.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
JAM3	NM_032801.5	c.2T>A	p.Met1?	start_lost	1/9	ENST00000299106.9
JAM3	NM_001205329.2	c.2T>A	p.Met1?	start_lost	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
JAM3	ENST00000299106.9	c.2T>A	p.Met1?	start_lost	1/9	1	NM_032801.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458514 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725662

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Porencephaly-microcephaly-bilateral congenital cataract syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 05, 2020

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	24
Dann	Benign	0.95
DEOGEN2	Benign	0.082	T;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.39	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.26	N;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.97	D;.;.
Vest4		0.88
MutPred		0.59		Gain of MoRF binding (P = 0.032);Gain of MoRF binding (P = 0.032);Gain of MoRF binding (P = 0.032);
MVP		0.88
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.86

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: rs397514678; hg19: chr11-133938980;