chr1-147908094-G-A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate

The NM_005267.5(GJA8):​c.139G>A​(p.Asp47Asn) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D47H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

GJA8
NM_005267.5 missense

Scores

16
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.92

Publications

43 publications found
Variant links:
Genes affected
GJA8 (HGNC:4281): (gap junction protein alpha 8) This gene encodes a transmembrane connexin protein that is necessary for lens growth and maturation of lens fiber cells. The encoded protein is a component of gap junction channels and functions in a calcium and pH-dependent manner. Mutations in this gene have been associated with zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. [provided by RefSeq, Dec 2009]
GJA8 Gene-Disease associations (from GenCC):
  • cataract 1 multiple types
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
  • cataract - microcornea syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • early-onset nuclear cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • early-onset sutural cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • pulverulent cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • total early-onset cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005267.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-147908094-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 280147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Trascript score misZ: -0.35816 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 1 multiple types, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset sutural cataract, pulverulent cataract, total early-onset cataract.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 1-147908094-G-A is Pathogenic according to our data. Variant chr1-147908094-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8727.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJA8NM_005267.5 linkc.139G>A p.Asp47Asn missense_variant Exon 2 of 2 ENST00000369235.2 NP_005258.2 P48165X5D7G1
GJA8XM_011509417.3 linkc.139G>A p.Asp47Asn missense_variant Exon 1 of 2 XP_011507719.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJA8ENST00000369235.2 linkc.139G>A p.Asp47Asn missense_variant Exon 2 of 2 6 NM_005267.5 ENSP00000358238.1 P48165

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
35
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cataract 1 multiple types Pathogenic:2
Mar 01, 2011
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Jan 21, 2023
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PS4(Moderate), PM1(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:18006672;21174522;21921990;26004348;30262699;28544770;28526010. The cataract phenotype/s reported for this variant are: Nuclear, Pulverulent nuclear, Nuclear with punctiform opacities, Zonular, and Perinuclear. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.94
D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
3.3
M
PhyloP100
9.9
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-5.0
D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.97
MutPred
0.95
Gain of catalytic residue at D47 (P = 0.1938);
MVP
0.96
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.84
gMVP
0.98
Mutation Taster
=2/98
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434643; hg19: chr1-147380221; API