16-57655473-C-G

Variant names:

• chr16-57655473-C-G
• rs1801257
• NM_201525.4:c.843C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_201525.4(ADGRG1):​c.843C>G​(p.Ser281Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.525 in 1,613,186 control chromosomes in the GnomAD database, including 231,092 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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. S281N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.62 (30963 hom., cov: 31)
  • Exomes 𝑓: 0.52 (200129 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.57
• Publications: 40 publications found

Genes affected

ADGRG1 (HGNC:4512): (adhesion G protein-coupled receptor G1) This gene encodes a member of the G protein-coupled receptor family and regulates brain cortical patterning. The encoded protein binds specifically to transglutaminase 2, a component of tissue and tumor stroma implicated as an inhibitor of tumor progression. Mutations in this gene are associated with a brain malformation known as bilateral frontoparietal polymicrogyria. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

ADGRG1 Gene-Disease associations (from GenCC):

• bilateral frontoparietal polymicrogyria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2816151E-6).
• BP6: Variant 16-57655473-C-G is Benign according to our data. Variant chr16-57655473-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.824 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201525.4. 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
	ADGRG1	NM_201525.4	MANE Select	c.843C>G	p.Ser281Arg	missense	Exon 6 of 14	NP_958933.1
	ADGRG1	NM_001145771.3		c.843C>G	p.Ser281Arg	missense	Exon 7 of 15	NP_001139243.1
	ADGRG1	NM_001370428.1		c.843C>G	p.Ser281Arg	missense	Exon 7 of 15	NP_001357357.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.843C>G	p.Ser281Arg	missense	Exon 6 of 14	ENSP00000455351.2
	ADGRG1	ENST00000567835.5	TSL:1	c.843C>G	p.Ser281Arg	missense	Exon 7 of 15	ENSP00000456794.1
	ADGRG1	ENST00000388813.9	TSL:1	c.843C>G	p.Ser281Arg	missense	Exon 7 of 15	ENSP00000373465.5

Frequencies

GnomAD3 genomes AF: 0.620 AC: 94104 AN: 151866 Hom.: 30924 Cov.: 31

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.649

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.574

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.595 AC: 149196 AN: 250900 AF XY: 0.579

Gnomad AFR exome AF: 0.838

Gnomad AMR exome AF: 0.744

Gnomad ASJ exome AF: 0.515

Gnomad EAS exome AF: 0.855

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.489

Gnomad OTH exome AF: 0.557

GnomAD4 exome AF: 0.515 AC: 752706 AN: 1461204 Hom.: 200129 Cov.: 46 AF XY: 0.514 AC XY: 373892 AN XY: 726926

African (AFR) AF: 0.838 AC: 28048 AN: 33478

American (AMR) AF: 0.737 AC: 32934 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 13467 AN: 26128

East Asian (EAS) AF: 0.814 AC: 32327 AN: 39698

South Asian (SAS) AF: 0.559 AC: 48246 AN: 86254

European-Finnish (FIN) AF: 0.583 AC: 30946 AN: 53076

Middle Eastern (MID) AF: 0.459 AC: 2645 AN: 5766

European-Non Finnish (NFE) AF: 0.478 AC: 531921 AN: 1111710

Other (OTH) AF: 0.533 AC: 32172 AN: 60378

GnomAD4 genome AF: 0.620 AC: 94203 AN: 151982 Hom.: 30963 Cov.: 31 AF XY: 0.627 AC XY: 46534 AN XY: 74248

African (AFR) AF: 0.824 AC: 34196 AN: 41476

American (AMR) AF: 0.649 AC: 9912 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1783 AN: 3472

East Asian (EAS) AF: 0.844 AC: 4349 AN: 5150

South Asian (SAS) AF: 0.572 AC: 2747 AN: 4800

European-Finnish (FIN) AF: 0.602 AC: 6345 AN: 10548

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 32947 AN: 67944

Other (OTH) AF: 0.584 AC: 1233 AN: 2112

Alfa AF: 0.494 Hom.: 11328

Bravo AF: 0.637

TwinsUK AF: 0.481 AC: 1784

ALSPAC AF: 0.471 AC: 1814

ESP6500AA AF: 0.824 AC: 3624

ESP6500EA AF: 0.493 AC: 4241

ExAC AF: 0.591 AC: 71777

Asia WGS AF: 0.729 AC: 2535 AN: 3478

EpiCase AF: 0.488

EpiControl AF: 0.496

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Bilateral frontoparietal polymicrogyria (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0060
DANN	Benign	0.20
DEOGEN2	Benign	0.071	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0035	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.019
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.14		Loss of phosphorylation at S281 (P = 0.0193)
ClinPred		0.0083	T
GERP RS		-6.2
Varity_R		0.027
gMVP		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801257; hg19: chr16-57689385; COSMIC: COSV65636299; COSMIC: COSV65636299;