6-68956768-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001704.3(ADGRB3):c.1484C>T(p.Thr495Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,461,660 control chromosomes in the GnomAD database, including 1 homozygotes. 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)
  • Exomes 𝑓: 0.000039 (1 hom.)
• Consequence: ADGRB3 NM_001704.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23091146).
• BS2: High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADGRB3	NM_001704.3	c.1484C>T	p.Thr495Met	missense_variant	8/32	ENST00000370598.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADGRB3	ENST00000370598.6	c.1484C>T	p.Thr495Met	missense_variant	8/32	1	NM_001704.3	P1
ADGRB3	ENST00000546190.5	c.1484C>T	p.Thr495Met	missense_variant	6/30	1		P1
ADGRB3	ENST00000684661.1	c.1484C>T	p.Thr495Met	missense_variant, NMD_transcript_variant	8/32

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251234 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461660 Hom.: 1 Cov.: 33 AF XY: 0.0000385 AC XY: 28 AN XY: 727116

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

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

Jul 26, 2022

The c.1484C>T (p.T495M) alteration is located in exon 8 (coding exon 6) of the ADGRB3 gene. This alteration results from a C to T substitution at nucleotide position 1484, causing the threonine (T) at amino acid position 495 to be replaced by a methionine (M). 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	0.092
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	0.022
Eigen_PC	Benign	-0.087
FATHMM_MKL	Benign	0.41	N
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.83	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.18
Sift	Benign	0.044	D;.
Sift4G	Uncertain	0.021	D;D
Polyphen		1.0	D;D
Vest4		0.37
MVP		0.043
MPC		0.59
ClinPred		0.35	T
GERP RS		5.2
Varity_R		0.098
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113677156; hg19: chr6-69666660; COSMIC: COSV65405340;