12-130992264-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_198827.5(ADGRD1):ā€‹c.838A>Cā€‹(p.Ile280Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I280V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ADGRD1
NM_198827.5 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.93
Variant links:
Genes affected
ADGRD1 (HGNC:19893): (adhesion G protein-coupled receptor D1) The adhesion G-protein-coupled receptors (GPCRs), including GPR133, are membrane-bound proteins with long N termini containing multiple domains. GPCRs, or GPRs, contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins (summary by Bjarnadottir et al., 2004 [PubMed 15203201]).[supplied by OMIM, Nov 2010]
ADGRD1-AS1 (HGNC:53314): (ADGRD1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28755182).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ADGRD1NM_198827.5 linkuse as main transcriptc.838A>C p.Ile280Leu missense_variant 8/25 ENST00000261654.10
ADGRD1-AS1NR_131951.1 linkuse as main transcriptn.70-1127T>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ADGRD1ENST00000261654.10 linkuse as main transcriptc.838A>C p.Ile280Leu missense_variant 8/251 NM_198827.5 P4Q6QNK2-1
ADGRD1-AS1ENST00000542980.1 linkuse as main transcriptn.277+85T>G intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250806
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135532
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461184
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726826
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 26, 2023The c.838A>C (p.I280L) alteration is located in exon 8 (coding exon 8) of the ADGRD1 gene. This alteration results from a A to C substitution at nucleotide position 838, causing the isoleucine (I) at amino acid position 280 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
0.17
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.037
T;T;.
Eigen
Benign
0.023
Eigen_PC
Benign
0.0011
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Benign
0.80
T;D;T
M_CAP
Benign
0.0081
T
MetaRNN
Benign
0.29
T;T;T
MetaSVM
Benign
-0.99
T
MutationTaster
Benign
0.66
D;D
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-0.62
N;N;N
REVEL
Benign
0.18
Sift
Benign
0.063
T;D;T
Sift4G
Uncertain
0.021
D;D;D
Polyphen
0.86
P;.;.
Vest4
0.26
MutPred
0.49
Loss of helix (P = 0.0123);.;.;
MVP
0.40
MPC
0.18
ClinPred
0.58
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.40

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: rs949956077; hg19: chr12-131476809; API