6-68639360-T-C

Variant names:

• chr6-68639360-T-C
• NM_001704.3:c.685T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001704.3(ADGRB3):​c.685T>C​(p.Cys229Arg) 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. 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: 7.61

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRB3	NM_001704.3	c.685T>C	p.Cys229Arg	missense_variant	Exon 3 of 32	ENST00000370598.6	NP_001695.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRB3	ENST00000370598.6	c.685T>C	p.Cys229Arg	missense_variant	Exon 3 of 32	1	NM_001704.3	ENSP00000359630.1
ADGRB3	ENST00000546190.5	c.685T>C	p.Cys229Arg	missense_variant	Exon 1 of 30	1		ENSP00000441821.2
ADGRB3	ENST00000684661.1	n.685T>C		non_coding_transcript_exon_variant	Exon 3 of 32			ENSP00000507613.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685T>C (p.C229R) alteration is located in exon 3 (coding exon 1) of the ADGRB3 gene. This alteration results from a T to C substitution at nucleotide position 685, causing the cysteine (C) at amino acid position 229 to be replaced by an arginine (R). 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	.;T
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.017	D;D
Polyphen		0.98	D;D
Vest4		0.95
MutPred		0.79		Loss of catalytic residue at L230 (P = 0.0082);Loss of catalytic residue at L230 (P = 0.0082);
MVP		0.14
MPC		1.1
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.94
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr6-69349252;