rs114249403

Variant names:

• chr11-134139806-G-A
• rs114249403
• NM_032801.5:c.77-45G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032801.5(JAM3):​c.77-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,504,462 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (15 hom.)
• Consequence: JAM3 NM_032801.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.118
• Publications: 0 publications found

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]

JAM3 Gene-Disease associations (from GenCC):

• porencephaly-microcephaly-bilateral congenital cataract syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 11-134139806-G-A is Benign according to our data. Variant chr11-134139806-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1201266.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00735 (1120/152304) while in subpopulation AFR AF = 0.025 (1041/41570). AF 95% confidence interval is 0.0238. There are 9 homozygotes in GnomAd4. There are 546 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032801.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAM3	NM_032801.5	MANE Select	c.77-45G>A		intron	N/A	NP_116190.3
	JAM3	NM_001205329.2		c.77-45G>A		intron	N/A	NP_001192258.1	Q9BX67-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAM3	ENST00000299106.9	TSL:1 MANE Select	c.77-45G>A		intron	N/A	ENSP00000299106.4	Q9BX67-1
	JAM3	ENST00000963685.1		c.77-45G>A		intron	N/A	ENSP00000633744.1
	JAM3	ENST00000876942.1		c.77-45G>A		intron	N/A	ENSP00000547001.1

Frequencies

GnomAD3 genomes AF: 0.00731 AC: 1112 AN: 152186 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00956

GnomAD2 exomes AF: 0.00199 AC: 501 AN: 251350 AF XY: 0.00151

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000880 AC: 1190 AN: 1352158 Hom.: 15 Cov.: 20 AF XY: 0.000777 AC XY: 528 AN XY: 679390

African (AFR) AF: 0.0247 AC: 774 AN: 31324

American (AMR) AF: 0.00182 AC: 81 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39166

South Asian (SAS) AF: 0.0000714 AC: 6 AN: 84050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.000901 AC: 5 AN: 5550

European-Non Finnish (NFE) AF: 0.000234 AC: 237 AN: 1012002

Other (OTH) AF: 0.00151 AC: 86 AN: 56770

GnomAD4 genome AF: 0.00735 AC: 1120 AN: 152304 Hom.: 9 Cov.: 32 AF XY: 0.00733 AC XY: 546 AN XY: 74464

African (AFR) AF: 0.0250 AC: 1041 AN: 41570

American (AMR) AF: 0.00288 AC: 44 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.00946 AC: 20 AN: 2114

Alfa AF: 0.00346 Hom.: 2

Bravo AF: 0.00795

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.71
DANN	Benign	0.75
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs114249403; hg19: chr11-134009701;