NM_021954.4:c.82_84delGTGinsCTT

Variant names:

• chr13-20143205-CAC-AAG
• NM_021954.4:c.82_84delGTGinsCTT
• GJA3 p.Val28Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM5 PP2 PP3

The NM_021954.4(GJA3):​c.82_84delGTGinsCTT​(p.Val28Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V28M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GJA3 NM_021954.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.20
• Publications: 0 publications found

Genes affected

GJA3 (HGNC:4277): (gap junction protein alpha 3) The protein encoded by this gene is a connexin and is a component of lens fiber gap junctions. Defects in this gene are a cause of zonular pulverulent cataract type 3 (CZP3). [provided by RefSeq, Jan 2010]

GJA3 Gene-Disease associations (from GenCC):

• cataract 14 multiple types

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset posterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pulverulent cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000299362 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_021954.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20143207-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 468544.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.7112 (below the threshold of 3.09). Trascript score misZ: -0.026578 (below the threshold of 3.09). GenCC associations: The gene is linked to cataract 14 multiple types, early-onset nuclear cataract, pulverulent cataract, early-onset posterior polar cataract.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021954.4. 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
	GJA3	NM_021954.4	MANE Select	c.82_84delGTGinsCTT	p.Val28Leu	missense	N/A	NP_068773.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA3	ENST00000241125.4	TSL:3 MANE Select	c.82_84delGTGinsCTT	p.Val28Leu	missense	N/A	ENSP00000241125.3	Q9Y6H8
	GJA3	ENST00000890229.1		c.82_84delGTGinsCTT	p.Val28Leu	missense	N/A	ENSP00000560288.1
	GJA3	ENST00000890230.1		c.82_84delGTGinsCTT	p.Val28Leu	missense	N/A	ENSP00000560289.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr13-20717344;