chr12-130981994-G-A

Position:

• chr12-130981994-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198827.5(ADGRD1):​c.421G>A​(p.Gly141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G141D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADGRD1 NM_198827.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09887195).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRD1	NM_198827.5	c.421G>A	p.Gly141Ser	missense_variant	5/25	ENST00000261654.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRD1	ENST00000261654.10	c.421G>A	p.Gly141Ser	missense_variant	5/25	1	NM_198827.5	P4
ADGRD1	ENST00000535015.5	c.517G>A	p.Gly173Ser	missense_variant	6/26	1		A1
ADGRD1	ENST00000542091.5	c.311-5101G>A		intron_variant		3
ADGRD1	ENST00000541143.5	n.5891G>A		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The c.421G>A (p.G141S) alteration is located in exon 5 (coding exon 5) of the ADGRD1 gene. This alteration results from a G to A substitution at nucleotide position 421, causing the glycine (G) at amino acid position 141 to be replaced by a serine (S). 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	0.075
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.20
Sift	Benign	0.17	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.051	B;.
Vest4		0.10
MutPred		0.36		Loss of sheet (P = 7e-04);.;
MVP		0.48
MPC		0.18
ClinPred		0.10	T
GERP RS		3.3
Varity_R		0.050
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-131466539; COSMIC: COSV55453800; COSMIC: COSV55453800;