6-68638970-A-G

Variant names:

• chr6-68638970-A-G
• rs1031211547
• NM_001704.3:c.295A>G

Variant summary

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

The NM_001704.3(ADGRB3):​c.295A>G​(p.Lys99Glu) 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. 12/20 in silico tools predict 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: 5.56

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=0.17069188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRB3	NM_001704.3	c.295A>G	p.Lys99Glu	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.295A>G	p.Lys99Glu	missense_variant	Exon 3 of 32	1	NM_001704.3	ENSP00000359630.1
ADGRB3	ENST00000546190.5	c.295A>G	p.Lys99Glu	missense_variant	Exon 1 of 30	1		ENSP00000441821.2
ADGRB3	ENST00000684661.1	n.295A>G		non_coding_transcript_exon_variant	Exon 3 of 32			ENSP00000507613.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.295A>G (p.K99E) alteration is located in exon 3 (coding exon 1) of the ADGRB3 gene. This alteration results from a A to G substitution at nucleotide position 295, causing the lysine (K) at amino acid position 99 to be replaced by a glutamic acid (E). 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	0.085
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.030	N;.
REVEL	Benign	0.046
Sift	Benign	0.15	T;.
Sift4G	Benign	0.28	T;T
Polyphen		0.0090	B;B
Vest4		0.53
MutPred		0.34		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.043
MPC		0.30
ClinPred		0.62	D
GERP RS		5.3
Varity_R		0.12
gMVP		0.36

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: rs1031211547; hg19: chr6-69348862;