rs80358204

chr1-147908086-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_005267.5(GJA8):c.131T>A(p.Val44Glu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V44M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA8 NM_005267.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.95

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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, 4 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 chr1-147908085-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1704073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 1-147908086-T-A is Pathogenic according to our data. Variant chr1-147908086-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 8725.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-147908086-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJA8	NM_005267.5	c.131T>A	p.Val44Glu	missense_variant	2/2	ENST00000369235.2
GJA8	XM_011509417.3	c.131T>A	p.Val44Glu	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJA8	ENST00000369235.2	c.131T>A	p.Val44Glu	missense_variant	2/2		NM_005267.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataract 1 multiple types Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 23, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.95		Gain of disorder (P = 0.0052);
MVP		0.94
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.91
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs80358204; hg19: chr1-147380213;