chr1-147907897-G-T

Variant names:

• chr1-147907897-G-T
• rs115981722
• NM_005267.5:c.-11-48G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005267.5(GJA8):​c.-11-48G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0363 in 1,301,272 control chromosomes in the GnomAD database, including 1,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (83 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1016 hom.)
• Consequence: GJA8 NM_005267.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.210
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-147907897-G-T is Benign according to our data. Variant chr1-147907897-G-T is described in ClinVar as Benign. ClinVar VariationId is 1273241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0291 (4425/152200) while in subpopulation NFE AF = 0.0457 (3111/68010). AF 95% confidence interval is 0.0444. There are 83 homozygotes in GnomAd4. There are 2153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 83 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005267.5. 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
	GJA8	NM_005267.5	MANE Select	c.-11-48G>T		intron	N/A	NP_005258.2	P48165

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	ENST00000369235.2	TSL:6 MANE Select	c.-11-48G>T		intron	N/A	ENSP00000358238.1	P48165

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4425 AN: 152082 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.00748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0216

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00602

Gnomad FIN AF: 0.0512

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0373 AC: 42864 AN: 1149072 Hom.: 1016 AF XY: 0.0364 AC XY: 21330 AN XY: 585972

African (AFR) AF: 0.00599 AC: 166 AN: 27734

American (AMR) AF: 0.0138 AC: 614 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 460 AN: 24276

East Asian (EAS) AF: 0.0000522 AC: 2 AN: 38336

South Asian (SAS) AF: 0.00596 AC: 477 AN: 80034

European-Finnish (FIN) AF: 0.0522 AC: 2584 AN: 49504

Middle Eastern (MID) AF: 0.00322 AC: 15 AN: 4664

European-Non Finnish (NFE) AF: 0.0445 AC: 36924 AN: 830210

Other (OTH) AF: 0.0325 AC: 1622 AN: 49982

GnomAD4 genome AF: 0.0291 AC: 4425 AN: 152200 Hom.: 83 Cov.: 32 AF XY: 0.0289 AC XY: 2153 AN XY: 74392

African (AFR) AF: 0.00746 AC: 310 AN: 41540

American (AMR) AF: 0.0216 AC: 330 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00603 AC: 29 AN: 4812

European-Finnish (FIN) AF: 0.0512 AC: 542 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0457 AC: 3111 AN: 68010

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0405 Hom.: 22

Bravo AF: 0.0250

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.7
DANN	Benign	0.72
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs115981722; hg19: chr1-147380024;