4-22387745-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000334304.10(ADGRA3):ā€‹c.3926A>Gā€‹(p.Asn1309Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000013 ( 0 hom. )

Consequence

ADGRA3
ENST00000334304.10 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.17
Variant links:
Genes affected
ADGRA3 (HGNC:13839): (adhesion G protein-coupled receptor A3) This gene encodes a member of the G protein-coupled receptor superfamily. This membrane protein may play a role in tumor angiogenesis through its interaction with the human homolog of the Drosophila disc large tumor suppressor gene. This gene is mapped to a candidate region of chromosome 4 which may be associated with bipolar disorder and schizophrenia. [provided by RefSeq, Oct 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.044020712).
BS2
High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADGRA3NM_145290.4 linkuse as main transcriptc.3926A>G p.Asn1309Ser missense_variant 19/19 ENST00000334304.10 NP_660333.2
ADGRA3XM_047449703.1 linkuse as main transcriptc.3335A>G p.Asn1112Ser missense_variant 19/19 XP_047305659.1
ADGRA3XM_047449704.1 linkuse as main transcriptc.3335A>G p.Asn1112Ser missense_variant 19/19 XP_047305660.1
ADGRA3XM_011513811.3 linkuse as main transcriptc.3248A>G p.Asn1083Ser missense_variant 14/14 XP_011512113.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADGRA3ENST00000334304.10 linkuse as main transcriptc.3926A>G p.Asn1309Ser missense_variant 19/191 NM_145290.4 ENSP00000334952 P1Q8IWK6-1
ADGRA3ENST00000282943.9 linkuse as main transcriptn.3497A>G non_coding_transcript_exon_variant 17/171
ADGRA3ENST00000499527.6 linkuse as main transcriptn.3623A>G non_coding_transcript_exon_variant 3/31
ADGRA3ENST00000511051.5 linkuse as main transcriptc.104+1343A>G intron_variant, NMD_transcript_variant 3 ENSP00000424927

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250740
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135518
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461176
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
726800
show subpopulations
Gnomad4 AFR exome
AF:
0.0000897
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000900
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 25, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ADGRA3-related conditions. This variant is present in population databases (rs144907660, gnomAD 0.003%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1309 of the ADGRA3 protein (p.Asn1309Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
16
DANN
Benign
0.92
DEOGEN2
Benign
0.18
T
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.13
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.044
T
MetaSVM
Benign
-0.98
T
MutationTaster
Benign
0.97
D
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.97
N
REVEL
Benign
0.092
Sift
Benign
0.53
T
Sift4G
Benign
0.53
T
Polyphen
0.0060
B
Vest4
0.085
MVP
0.068
MPC
0.081
ClinPred
0.073
T
GERP RS
4.5
Varity_R
0.027
gMVP
0.22

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: rs144907660; hg19: chr4-22389368; API