Genetic Variant GJA9:p.Ile505Leu (chr1-38874586-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_030772.5(GJA9):c.1513A>C(p.Ile505Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GJA9
NM_030772.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.22

Variant links:

Genes affected

GJA9 (HGNC:19155): (gap junction protein alpha 9) Connexins, such as GJA9, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).[supplied by OMIM, Mar 2008]

GJA9 links:

ENSG00000274944 (HGNC:):

ENSG00000274944 links:

RRAGC-DT (HGNC:55793): (RRAGC divergent transcript)

RRAGC-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.097964704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJA9	NM_030772.5 link	c.1513A>C	p.Ile505Leu	missense_variant	Exon 2 of 2	ENST00000357771.5	NP_110399.2	P57773-1A0A654IBV8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJA9	ENST00000357771.5 link	c.1513A>C	p.Ile505Leu	missense_variant	Exon 2 of 2	1	NM_030772.5	ENSP00000350415.3		P57773-1
ENSG00000274944	ENST00000621281.1 link	c.37-1496A>C		intron_variant	Intron 1 of 4	2		ENSP00000479064.1		A0A087WV05

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152048

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00700

AC:

9852

AN:

1407872

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

4521

AN XY:

702216

show subpopulations

Gnomad4 AFR exome

AF:

0.00614

Gnomad4 AMR exome

AF:

0.000359

Gnomad4 ASJ exome

AF:

0.00249

Gnomad4 EAS exome

AF:

0.00149

Gnomad4 SAS exome

AF:

0.00233

Gnomad4 FIN exome

AF:

0.000397

Gnomad4 NFE exome

AF:

0.00842

Gnomad4 OTH exome

AF:

0.00549

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000947

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1513A>C (p.I505L) alteration is located in exon 2 (coding exon 1) of the GJA9 gene. This alteration results from a A to C substitution at nucleotide position 1513, causing the isoleucine (I) at amino acid position 505 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

9.3

DANN

Benign

0.93

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.40

.;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.098

T;T

MetaSVM

Uncertain

0.088

MutationAssessor

Benign

1.6

L;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.080

N;N

REVEL

Benign

0.26

Sift

Benign

0.11

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.020

B;B

Vest4

0.15

MutPred

0.26

Gain of disorder (P = 0.0767);Gain of disorder (P = 0.0767);

MVP

0.14

MPC

0.071

ClinPred

0.33

GERP RS

2.8

Varity_R

0.15

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over