rs587777304

Variant names:

• chr1-147759016-T-A
• rs587777304
• NM_181703.4:c.223A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-147759016-T-A
• chr1-147759016-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_181703.4(GJA5):​c.223A>T​(p.Ile75Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I75S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJA5 NM_181703.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.94
• Publications: 6 publications found

Genes affected

GJA5 (HGNC:4279): (gap junction protein alpha 5) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

GJA5 Gene-Disease associations (from GenCC):

• atrial fibrillation, familial, 11

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• heart conduction disease

  Inheritance: AD Classification: LIMITED Submitted by: Genomics England PanelApp

ENSG00000294222 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 1.5546 (below the threshold of 3.09). GenCC associations: The gene is linked to atrial fibrillation, familial, 11, heart conduction disease, familial atrial fibrillation.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181703.4. 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
	GJA5	NM_181703.4	MANE Select	c.223A>T	p.Ile75Phe	missense	Exon 2 of 2	NP_859054.1
	GJA5	NM_005266.7		c.223A>T	p.Ile75Phe	missense	Exon 2 of 2	NP_005257.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJA5	ENST00000579774.3	TSL:1 MANE Select	c.223A>T	p.Ile75Phe	missense	Exon 2 of 2	ENSP00000463851.1
	GJA5	ENST00000621517.1	TSL:2	c.223A>T	p.Ile75Phe	missense	Exon 2 of 2	ENSP00000484552.1
	GJA5	ENST00000863529.1		c.223A>T	p.Ile75Phe	missense	Exon 2 of 2	ENSP00000533588.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Atrial fibrillation, familial, 11 (1)
-	1	-	Atrial fibrillation, familial, 11;C4551959:Atrial standstill 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.86
Sift	Benign	0.039	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.83	P
Vest4		0.49
MutPred		0.64		Loss of helix (P = 0.1299)
MVP		0.99
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.39
gMVP		0.98

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: rs587777304; hg19: chr1-147231124;