8-142464809-A-C

Position:

• chr8-142464809-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001702.3(ADGRB1):​c.611A>C​(p.His204Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,382,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADGRB1 NM_001702.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

Genes affected

ADGRB1 (HGNC:943): (adhesion G protein-coupled receptor B1) Angiogenesis is controlled by a local balance between stimulators and inhibitors of new vessel growth and is suppressed under normal physiologic conditions. Angiogenesis has been shown to be essential for growth and metastasis of solid tumors. In order to obtain blood supply for their growth, tumor cells are potently angiogenic and attract new vessels as results of increased secretion of inducers and decreased production of endogenous negative regulators. BAI1 contains at least one 'functional' p53-binding site within an intron, and its expression has been shown to be induced by wildtype p53. There are two other brain-specific angiogenesis inhibitor genes, designated BAI2 and BAI3 which along with BAI1 have similar tissue specificities and structures, however only BAI1 is transcriptionally regulated by p53. BAI1 is postulated to be a member of the secretin receptor family, an inhibitor of angiogenesis and a growth suppressor of glioblastomas [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41816494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRB1	NM_001702.3	c.611A>C	p.His204Pro	missense_variant	2/31	ENST00000517894.6	NP_001693.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRB1	ENST00000517894.6	c.611A>C	p.His204Pro	missense_variant	2/31	5	NM_001702.3	ENSP00000430945.1
ADGRB1	ENST00000521208.5	n.611A>C		non_coding_transcript_exon_variant	2/30	5		ENSP00000427783.1
ADGRB1	ENST00000643448.1	c.611A>C	p.His204Pro	missense_variant	2/31			ENSP00000494563.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1382410 Hom.: 0 Cov.: 34 AF XY: 0.00000147 AC XY: 1 AN XY: 682296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Mar 15, 2024

The c.611A>C (p.H204P) alteration is located in exon 1 (coding exon 1) of the ADGRB1 gene. This alteration results from a A to C substitution at nucleotide position 611, causing the histidine (H) at amino acid position 204 to be replaced by a proline (P). 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	0.31
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	.;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	.;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.012	.;D;D
Sift4G	Uncertain	0.034	.;D;D
Vest4		0.39, 0.37
MutPred		0.70		Gain of glycosylation at H204 (P = 0.0355);Gain of glycosylation at H204 (P = 0.0355);Gain of glycosylation at H204 (P = 0.0355);
MVP		0.10
MPC		1.5
ClinPred		0.86	D
GERP RS		4.4
Varity_R		0.59
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-143546170;