chr1-147903563-A-G

Variant names:

• chr1-147903563-A-G
• rs9437983
• NM_005267.5:c.-12+702A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005267.5(GJA8):​c.-12+702A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 152,096 control chromosomes in the GnomAD database, including 7,076 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (7076 hom., cov: 32)
• Consequence: GJA8 NM_005267.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.162
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA8	NM_005267.5	c.-12+702A>G		intron_variant	Intron 1 of 1	ENST00000369235.2	NP_005258.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA8	ENST00000369235.2	c.-12+702A>G		intron_variant	Intron 1 of 1	6	NM_005267.5	ENSP00000358238.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45546 AN: 151978 Hom.: 7060 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.282

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.298

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.245

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.330

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.300 AC: 45598 AN: 152096 Hom.: 7076 Cov.: 32 AF XY: 0.299 AC XY: 22195 AN XY: 74352

African (AFR) AF: 0.250 AC: 10370 AN: 41486

American (AMR) AF: 0.402 AC: 6139 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 1034 AN: 3468

East Asian (EAS) AF: 0.383 AC: 1976 AN: 5160

South Asian (SAS) AF: 0.186 AC: 896 AN: 4826

European-Finnish (FIN) AF: 0.262 AC: 2769 AN: 10588

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.314 AC: 21378 AN: 67980

Other (OTH) AF: 0.333 AC: 701 AN: 2106

Alfa AF: 0.305 Hom.: 1446

Bravo AF: 0.312

Asia WGS AF: 0.292 AC: 1014 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.0
DANN	Benign	0.51
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9437983; hg19: chr1-147375689;