6-68930622-G-C

Position:

• chr6-68930622-G-C

Variant summary

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

The NM_001704.3(ADGRB3):​c.821G>C​(p.Arg274Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRB3 NM_001704.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

Genes affected

ADGRB3 (HGNC:945): (adhesion G protein-coupled receptor B3) This p53-target gene encodes a brain-specific angiogenesis inhibitor, a seven-span transmembrane protein, and is thought to be a member of the secretin receptor family. Brain-specific angiogenesis proteins BAI2 and BAI3 are similar to BAI1 in structure, have similar tissue specificities, and may also play a role in angiogenesis. [provided by RefSeq, Jul 2008]

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=0.14850852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRB3	NM_001704.3	c.821G>C	p.Arg274Thr	missense_variant	4/32	ENST00000370598.6	NP_001695.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRB3	ENST00000370598.6	c.821G>C	p.Arg274Thr	missense_variant	4/32	1	NM_001704.3	ENSP00000359630	P1
ADGRB3	ENST00000546190.5	c.821G>C	p.Arg274Thr	missense_variant	2/30	1		ENSP00000441821	P1
ADGRB3	ENST00000684661.1	c.821G>C	p.Arg274Thr	missense_variant, NMD_transcript_variant	4/32			ENSP00000507613

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Feb 14, 2023

The c.821G>C (p.R274T) alteration is located in exon 4 (coding exon 2) of the ADGRB3 gene. This alteration results from a G to C substitution at nucleotide position 821, causing the arginine (R) at amino acid position 274 to be replaced by a threonine (T). 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	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.061	T;T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.045
Sift	Benign	0.11	T;.
Sift4G	Benign	0.14	T;T
Polyphen		0.018	B;B
Vest4		0.47
MutPred		0.36		Gain of glycosylation at R274 (P = 0.0132);Gain of glycosylation at R274 (P = 0.0132);
MVP		0.043
MPC		0.32
ClinPred		0.80	D
GERP RS		5.2
Varity_R		0.21
gMVP		0.27

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

Other links and lift over

dbSNP: rs748456125; hg19: chr6-69640514; COSMIC: COSV101001623;