NM_005267.5:c.151G>T

Variant names:

• chr1-147908106-G-T
• rs864309703
• NM_005267.5:c.151G>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_005267.5(GJA8):​c.151G>T​(p.Asp51Tyr) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D51N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.07
• Publications: 10 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: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr1-147908106-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217355.
• 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, 0.957
• PP5: Variant 1-147908106-G-T is Pathogenic according to our data. Variant chr1-147908106-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521485.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	NM_005267.5	MANE Select	c.151G>T	p.Asp51Tyr	missense	Exon 2 of 2	NP_005258.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA8	ENST00000369235.2	TSL:6 MANE Select	c.151G>T	p.Asp51Tyr	missense	Exon 2 of 2	ENSP00000358238.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Sep 07, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.65		Loss of glycosylation at S50 (P = 0.2431)
MVP		0.94
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.90
gMVP		0.98
Mutation Taster		=19/81	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

Other links and lift over

dbSNP: rs864309703; hg19: chr1-147380233;