Genetic Variant NM_001704.3:c.982G>C (chr6-68936632-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001704.3(ADGRB3):c.982G>C(p.Gly328Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ADGRB3
NM_001704.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.17

Publications

0 publications found

Variant links:

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]

ADGRB3 links:

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ACMG classification

Classification was made for transcript

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, 0.816

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRB3	NM_001704.3 link	c.982G>C	p.Gly328Arg	missense_variant	Exon 5 of 32	ENST00000370598.6	NP_001695.2	O60242-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADGRB3	ENST00000370598.6 link	c.982G>C	p.Gly328Arg	missense_variant	Exon 5 of 32	1	NM_001704.3	ENSP00000359630.1	O60242-1
ADGRB3	ENST00000546190.5 link	c.982G>C	p.Gly328Arg	missense_variant	Exon 3 of 30	1		ENSP00000441821.2	O60242-1
ADGRB3	ENST00000684661.1 link	n.982G>C		non_coding_transcript_exon_variant	Exon 5 of 32			ENSP00000507613.1	A0A804HJR2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726994

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111880

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Benign

-0.51

PhyloP100

8.2

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Uncertain

0.52

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 = 0.0269);Loss of catalytic residue at G328 (P = 0.0269);

MVP

0.17

MPC

0.76

ClinPred

1.0

GERP RS

5.4

Varity_R

0.78

gMVP

0.71

Mutation Taster

=28/72

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over