Genetic Variant GJD3:p.Met97Leu (chr17-40363527-T-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000578689.2(GJD3):c.289A>T(p.Met97Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,563,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

GJD3
ENST00000578689.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.374

Publications

2 publications found

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 links:

GJD3-AS1 (HGNC:56092): (GJD3 antisense RNA 1)

GJD3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03361708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD3	NM_152219.4 link	c.289A>T	p.Met97Leu	missense_variant	Exon 1 of 1	ENST00000578689.2	NP_689343.3	Q8N144-1A0A654IC68
GJD3-AS1	NR_186704.1 link	n.683T>A		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GJD3	ENST00000578689.2 link	c.289A>T	p.Met97Leu	missense_variant	Exon 1 of 1	6	NM_152219.4	ENSP00000463752.1	Q8N144-1
GJD3-AS1	ENST00000578774.1 link	n.928T>A		non_coding_transcript_exon_variant	Exon 2 of 2	4
GJD3-AS1	ENST00000791155.1 link	n.-43T>A		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000712

AC:

108

AN:

151622

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000953

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000595

AC:

AN:

164770

AF XY:

0.000506

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000647

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.00122

AC:

1717

AN:

1411416

Hom.:

Cov.:

AF XY:

0.00112

AC XY:

782

AN XY:

697516

show subpopulations

African (AFR)

AF:

0.000187

AC:

AN:

32158

American (AMR)

AF:

0.000270

AC:

AN:

36994

Ashkenazi Jewish (ASJ)

AF:

0.0000790

AC:

AN:

25332

East Asian (EAS)

AF:

0.00

AC:

AN:

36662

South Asian (SAS)

AF:

0.00

AC:

AN:

80148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00152

AC:

1656

AN:

1087236

Other (OTH)

AF:

0.000734

AC:

AN:

58580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000712

AC:

108

AN:

151742

Hom.:

Cov.:

AF XY:

0.000674

AC XY:

AN XY:

74188

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41468

American (AMR)

AF:

0.000328

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000953

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

67828

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00100

Hom.:

Bravo

AF:

0.000748

ESP6500AA

AF:

0.000257

AC:

ESP6500EA

AF:

0.000488

AC:

ExAC

AF:

0.000266

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.289A>T (p.M97L) alteration is located in exon 1 (coding exon 1) of the GJD3 gene. This alteration results from a A to T substitution at nucleotide position 289, causing the methionine (M) at amino acid position 97 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

0.15

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.41

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.20

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.034

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

0.62

PhyloP100

0.37

Sift4G

Benign

0.79

Polyphen

0.0080

Vest4

0.23

MutPred

0.32

Loss of catalytic residue at V93 (P = 0.0708);

MVP

0.34

MPC

1.2

ClinPred

0.031

GERP RS

-0.83

Varity_R

0.12

gMVP

0.25

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over