16-57566656-G-A

Variant names:

• chr16-57566656-G-A
• rs200838029
• NM_001304376.3:c.604G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001304376.3(ADGRG5):​c.604G>A​(p.Gly202Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,438,078 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G202W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ADGRG5 NM_001304376.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.20
• Publications: 2 publications found

Genes affected

ADGRG5 (HGNC:19010): (adhesion G protein-coupled receptor G5) This gene encodes a member of the adhesion family of G-protein coupled receptors. Members of this family are characterized by long N-termini and multiple functional domains. They may play a role in the immune system as well as in the central nervous system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

LOC105371291 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304376.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG5	NM_001304376.3	MANE Select	c.604G>A	p.Gly202Arg	missense	Exon 7 of 12	NP_001291305.1	Q8IZF4
	ADGRG5	NM_153837.4		c.604G>A	p.Gly202Arg	missense	Exon 7 of 12	NP_722579.1	Q8IZF4
	ADGRG5	NM_001318481.2		c.604G>A	p.Gly202Arg	missense	Exon 7 of 11	NP_001305410.1	B4E148

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG5	ENST00000349457.8	TSL:1 MANE Select	c.604G>A	p.Gly202Arg	missense	Exon 7 of 12	ENSP00000290823.4	Q8IZF4
	ADGRG5	ENST00000340339.4	TSL:1	c.604G>A	p.Gly202Arg	missense	Exon 7 of 12	ENSP00000342981.4	Q8IZF4
	ADGRG5	ENST00000897109.1		c.604G>A	p.Gly202Arg	missense	Exon 6 of 11	ENSP00000567168.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000433 AC: 1 AN: 230700 AF XY: 0.00000800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1438078 Hom.: 0 Cov.: 30 AF XY: 0.0000126 AC XY: 9 AN XY: 714544

African (AFR) AF: 0.00 AC: 0 AN: 32440

American (AMR) AF: 0.00 AC: 0 AN: 40310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25152

East Asian (EAS) AF: 0.00 AC: 0 AN: 38354

South Asian (SAS) AF: 0.00 AC: 0 AN: 82798

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52644

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1101326

Other (OTH) AF: 0.00 AC: 0 AN: 59370

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.22	D
PhyloP100		3.2
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.81		Gain of MoRF binding (P = 0.0101)
MVP		0.67
MPC		0.77
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.66
gMVP		0.69
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200838029; hg19: chr16-57600568; COSMIC: COSV61084547; COSMIC: COSV61084547;