6-68936632-G-T

Variant names:

• chr6-68936632-G-T
• rs145733293
• NM_001704.3:c.982G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_001704.3(ADGRB3):​c.982G>T​(p.Gly328Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G328S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADGRB3 NM_001704.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.17
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.8253 (below the threshold of 3.09). Trascript score misZ: 2.413 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRB3	NM_001704.3	c.982G>T	p.Gly328Cys	missense_variant	Exon 5 of 32	ENST00000370598.6	NP_001695.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRB3	ENST00000370598.6	c.982G>T	p.Gly328Cys	missense_variant	Exon 5 of 32	1	NM_001704.3	ENSP00000359630.1
ADGRB3	ENST00000546190.5	c.982G>T	p.Gly328Cys	missense_variant	Exon 3 of 30	1		ENSP00000441821.2
ADGRB3	ENST00000684661.1	n.982G>T		non_coding_transcript_exon_variant	Exon 5 of 32			ENSP00000507613.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Uncertain	-0.23	T
PhyloP100		8.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.5	D;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.72		Loss of catalytic residue at G328 (P = 0.0534);Loss of catalytic residue at G328 (P = 0.0534);
MVP		0.40
MPC		0.78
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.78
gMVP		0.76
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs145733293; hg19: chr6-69646524; COSMIC: COSV101002014;