16-57655474-G-C

Variant names:

• chr16-57655474-G-C
• rs146704802
• NM_201525.4:c.844G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201525.4(ADGRG1):​c.844G>C​(p.Gly282Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,613,802 control chromosomes in the GnomAD database, including 27 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G282E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (25 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.262
• Publications: 8 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026955605).
• BP6: Variant 16-57655474-G-C is Benign according to our data. Variant chr16-57655474-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00361 (550/152292) while in subpopulation NFE AF = 0.00541 (368/68024). AF 95% confidence interval is 0.00495. There are 2 homozygotes in GnomAd4. There are 283 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.844G>C	p.Gly282Arg	missense	Exon 6 of 14	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.844G>C	p.Gly282Arg	missense	Exon 7 of 15	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.844G>C	p.Gly282Arg	missense	Exon 7 of 15	NP_001357357.1	Q9Y653-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.844G>C	p.Gly282Arg	missense	Exon 6 of 14	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.844G>C	p.Gly282Arg	missense	Exon 7 of 15	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.844G>C	p.Gly282Arg	missense	Exon 7 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 550 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00541

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00400 AC: 1005 AN: 251098 AF XY: 0.00407

Gnomad AFR exome AF: 0.000678

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00561

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00444 AC: 6486 AN: 1461510 Hom.: 25 Cov.: 36 AF XY: 0.00437 AC XY: 3174 AN XY: 727074

African (AFR) AF: 0.000687 AC: 23 AN: 33478

American (AMR) AF: 0.000492 AC: 22 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00323 AC: 279 AN: 86254

European-Finnish (FIN) AF: 0.0106 AC: 563 AN: 53124

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00484 AC: 5378 AN: 1111938

Other (OTH) AF: 0.00321 AC: 194 AN: 60392

GnomAD4 genome AF: 0.00361 AC: 550 AN: 152292 Hom.: 2 Cov.: 33 AF XY: 0.00380 AC XY: 283 AN XY: 74450

African (AFR) AF: 0.000457 AC: 19 AN: 41558

American (AMR) AF: 0.000915 AC: 14 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.0108 AC: 115 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00541 AC: 368 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00357 Hom.: 1

Bravo AF: 0.00274

ExAC AF: 0.00426 AC: 517

EpiCase AF: 0.00420

EpiControl AF: 0.00451

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Bilateral frontoparietal polymicrogyria (2)
-	-	1	ADGRG1-related disorder (1)
-	-	1	Bilateral frontoparietal polymicrogyria;C3810405:Polymicrogyria, bilateral perisylvian, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.45
DANN	Benign	0.40
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.26
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.024
Sift	Benign	0.76	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.067
MutPred		0.36		Gain of solvent accessibility (P = 0.0023)
MVP		0.69
ClinPred		0.00029	T
GERP RS		0.75
Varity_R		0.017
gMVP		0.41
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146704802; hg19: chr16-57689386; COSMIC: COSV99059331; COSMIC: COSV99059331;