chr17-40363058-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_152219.4(GJD3):​c.758G>C​(p.Arg253Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,231,732 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.015 ( 31 hom., cov: 32)
Exomes 𝑓: 0.022 ( 286 hom. )

Consequence

GJD3
NM_152219.4 missense

Scores

1
11

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -5.51
Variant links:
Genes affected
GJD3 (HGNC:19147): (gap junction protein delta 3) This gene is a member of the large family of connexins that are required for the formation of gap junctions. Six connexin monomers form a hemichannel, or connexon, on the cell surface. This connexon can interact with a connexon from a neighboring cell, thus forming a channel linking the cytoplasm of the 2 cells. [provided by RefSeq, Jul 2008]
GJD3-AS1 (HGNC:56092): (GJD3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004409313).
BP6
Variant 17-40363058-C-G is Benign according to our data. Variant chr17-40363058-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3387757.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2287/150844) while in subpopulation NFE AF= 0.0228 (1541/67526). AF 95% confidence interval is 0.0219. There are 31 homozygotes in gnomad4. There are 1133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJD3NM_152219.4 linkc.758G>C p.Arg253Pro missense_variant Exon 1 of 1 ENST00000578689.2 NP_689343.3 Q8N144-1A0A654IC68
GJD3-AS1NR_186704.1 linkn.214C>G non_coding_transcript_exon_variant Exon 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJD3ENST00000578689.2 linkc.758G>C p.Arg253Pro missense_variant Exon 1 of 1 6 NM_152219.4 ENSP00000463752.1 Q8N144-1
GJD3-AS1ENST00000578774.1 linkn.484-25C>G intron_variant Intron 1 of 1 4

Frequencies

GnomAD3 genomes
AF:
0.0152
AC:
2288
AN:
150734
Hom.:
31
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00407
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.0181
Gnomad ASJ
AF:
0.00492
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00539
Gnomad FIN
AF:
0.0226
Gnomad MID
AF:
0.00955
Gnomad NFE
AF:
0.0228
Gnomad OTH
AF:
0.0155
GnomAD3 exomes
AF:
0.0321
AC:
12
AN:
374
Hom.:
1
AF XY:
0.0229
AC XY:
5
AN XY:
218
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0316
Gnomad OTH exome
AF:
0.100
GnomAD4 exome
AF:
0.0223
AC:
24086
AN:
1080888
Hom.:
286
Cov.:
33
AF XY:
0.0224
AC XY:
11489
AN XY:
513114
show subpopulations
Gnomad4 AFR exome
AF:
0.00316
Gnomad4 AMR exome
AF:
0.0130
Gnomad4 ASJ exome
AF:
0.00541
Gnomad4 EAS exome
AF:
0.0000385
Gnomad4 SAS exome
AF:
0.00549
Gnomad4 FIN exome
AF:
0.0207
Gnomad4 NFE exome
AF:
0.0243
Gnomad4 OTH exome
AF:
0.0192
GnomAD4 genome
AF:
0.0152
AC:
2287
AN:
150844
Hom.:
31
Cov.:
32
AF XY:
0.0154
AC XY:
1133
AN XY:
73716
show subpopulations
Gnomad4 AFR
AF:
0.00406
Gnomad4 AMR
AF:
0.0180
Gnomad4 ASJ
AF:
0.00492
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00539
Gnomad4 FIN
AF:
0.0226
Gnomad4 NFE
AF:
0.0228
Gnomad4 OTH
AF:
0.0153
Alfa
AF:
0.0164
Hom.:
6
Bravo
AF:
0.0139
ExAC
AF:
0.00298
AC:
21
Asia WGS
AF:
0.00233
AC:
8
AN:
3442

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Meniere disease Benign:1
Jan 09, 2024
Meniere Disease Neuroscience Research Program, Faculty of Medicine and Health, Kolling Institute, The University of Sydney
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: research

The NC_000017.11:g.40363058C>G, is a missense variant in GJD3 gene which produces an amino acid change from arginine to proline in the cytoplasmatic region of the connexon. The variant is part of an haplotype involved in Meniere’s Disease, composed by g.40356228C>T, g.40363058C>G, g.40363293G>A, g.40363294C>G and g.40363579G>T. The haplotype was found in 10 individuals with familial Meniere’s Disease, segregating in 3 of these families (PP1); and in another 8 individuals with sporadic Meniere’s Disease. GnomAD exomes allele frequency = 0.0223 is greater than 0.0001 (BS1); however, the frequency of the haplotype for the Iberian population in Spain is 0.0093. The variant was observed in healthy adults in gnomAD (BS2). The MetaRNN value of the variant is 0.0041 (BP4). In summary, this variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied: PP1,BS1,BS2,BP4. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.052
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
6.2
DANN
Benign
0.65
DEOGEN2
Benign
0.062
T
FATHMM_MKL
Benign
0.033
N
LIST_S2
Benign
0.39
T
MetaRNN
Benign
0.0044
T
MutationAssessor
Benign
0.34
N
PrimateAI
Uncertain
0.79
T
Sift4G
Benign
0.29
T
Polyphen
0.0
B
Vest4
0.092
MPC
1.7
GERP RS
-1.6
Varity_R
0.14
gMVP
0.19

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.

Other links and lift over

dbSNP: rs532965992; hg19: chr17-38519310; API