rs17379472

Variant names:

• chr16-57659586-T-C
• rs17379472
• NM_201525.4:c.1460T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201525.4(ADGRG1):​c.1460T>C​(p.Met487Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0341 in 1,614,038 control chromosomes in the GnomAD database, including 1,132 homozygotes. In-silico tool predicts 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. M487K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (88 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1044 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.95
• Publications: 14 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_201525.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.008508056).
• BP6: Variant 16-57659586-T-C is Benign according to our data. Variant chr16-57659586-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137495.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 = 0.0282 (4288/152268) while in subpopulation NFE AF = 0.0375 (2550/68022). AF 95% confidence interval is 0.0363. There are 88 homozygotes in GnomAd4. There are 2186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 88 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.1460T>C	p.Met487Thr	missense	Exon 11 of 14	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.1478T>C	p.Met493Thr	missense	Exon 12 of 15	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.1478T>C	p.Met493Thr	missense	Exon 12 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.1460T>C	p.Met487Thr	missense	Exon 11 of 14	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.1478T>C	p.Met493Thr	missense	Exon 12 of 15	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.1460T>C	p.Met487Thr	missense	Exon 12 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4286 AN: 152150 Hom.: 88 Cov.: 32

Gnomad AFR AF: 0.00637

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0295

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0727

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.0229

GnomAD2 exomes AF: 0.0328 AC: 8240 AN: 251372 AF XY: 0.0323

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0736

Gnomad NFE exome AF: 0.0400

Gnomad OTH exome AF: 0.0350

GnomAD4 exome AF: 0.0347 AC: 50760 AN: 1461770 Hom.: 1044 Cov.: 35 AF XY: 0.0341 AC XY: 24800 AN XY: 727194

African (AFR) AF: 0.00511 AC: 171 AN: 33480

American (AMR) AF: 0.0342 AC: 1528 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 401 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0165 AC: 1421 AN: 86258

European-Finnish (FIN) AF: 0.0686 AC: 3661 AN: 53390

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.0375 AC: 41742 AN: 1111928

Other (OTH) AF: 0.0293 AC: 1772 AN: 60386

GnomAD4 genome AF: 0.0282 AC: 4288 AN: 152268 Hom.: 88 Cov.: 32 AF XY: 0.0294 AC XY: 2186 AN XY: 74444

African (AFR) AF: 0.00636 AC: 264 AN: 41540

American (AMR) AF: 0.0296 AC: 453 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5174

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4826

European-Finnish (FIN) AF: 0.0727 AC: 772 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0375 AC: 2550 AN: 68022

Other (OTH) AF: 0.0227 AC: 48 AN: 2114

Alfa AF: 0.0339 Hom.: 312

Bravo AF: 0.0242

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0387 AC: 149

ESP6500AA AF: 0.00614 AC: 27

ESP6500EA AF: 0.0348 AC: 299

ExAC AF: 0.0319 AC: 3878

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0339

EpiControl AF: 0.0363

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Bilateral frontoparietal polymicrogyria (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.63	T
PhyloP100		6.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.53
Sift	Benign	0.044	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.93	P
Vest4		0.48
ClinPred		0.018	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.82
Mutation Taster		=28/72	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: rs17379472; hg19: chr16-57693498;