NM_201525.4:c.996T>C

Variant names:

• chr16-57655971-T-C
• rs1376041
• NM_201525.4:c.996T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_201525.4(ADGRG1):​c.996T>C​(p.Thr332Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.721 in 1,613,752 control chromosomes in the GnomAD database, including 423,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.79 (48353 hom., cov: 33)
  • Exomes 𝑓: 0.71 (375041 hom.)
• Consequence: ADGRG1 NM_201525.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.183
• Publications: 32 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 16-57655971-T-C is Benign according to our data. Variant chr16-57655971-T-C is described in ClinVar as Benign. ClinVar VariationId is 158641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.183 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.936 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.996T>C	p.Thr332Thr	synonymous	Exon 7 of 14	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.996T>C	p.Thr332Thr	synonymous	Exon 8 of 15	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.996T>C	p.Thr332Thr	synonymous	Exon 8 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.996T>C	p.Thr332Thr	synonymous	Exon 7 of 14	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.996T>C	p.Thr332Thr	synonymous	Exon 8 of 15	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.996T>C	p.Thr332Thr	synonymous	Exon 8 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes AF: 0.790 AC: 120161 AN: 152112 Hom.: 48301 Cov.: 33

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.735

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.773

GnomAD2 exomes AF: 0.759 AC: 190874 AN: 251354 AF XY: 0.745

Gnomad AFR exome AF: 0.951

Gnomad AMR exome AF: 0.893

Gnomad ASJ exome AF: 0.746

Gnomad EAS exome AF: 0.809

Gnomad FIN exome AF: 0.765

Gnomad NFE exome AF: 0.705

Gnomad OTH exome AF: 0.741

GnomAD4 exome AF: 0.714 AC: 1043920 AN: 1461522 Hom.: 375041 Cov.: 56 AF XY: 0.712 AC XY: 517343 AN XY: 727080

African (AFR) AF: 0.955 AC: 31979 AN: 33480

American (AMR) AF: 0.889 AC: 39756 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.740 AC: 19334 AN: 26136

East Asian (EAS) AF: 0.776 AC: 30816 AN: 39700

South Asian (SAS) AF: 0.675 AC: 58239 AN: 86254

European-Finnish (FIN) AF: 0.760 AC: 40497 AN: 53264

Middle Eastern (MID) AF: 0.706 AC: 4066 AN: 5758

European-Non Finnish (NFE) AF: 0.697 AC: 775287 AN: 1111818

Other (OTH) AF: 0.728 AC: 43946 AN: 60388

GnomAD4 genome AF: 0.790 AC: 120272 AN: 152230 Hom.: 48353 Cov.: 33 AF XY: 0.794 AC XY: 59129 AN XY: 74436

African (AFR) AF: 0.944 AC: 39238 AN: 41552

American (AMR) AF: 0.834 AC: 12762 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.735 AC: 2552 AN: 3472

East Asian (EAS) AF: 0.796 AC: 4119 AN: 5172

South Asian (SAS) AF: 0.681 AC: 3284 AN: 4824

European-Finnish (FIN) AF: 0.782 AC: 8285 AN: 10592

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.698 AC: 47457 AN: 67992

Other (OTH) AF: 0.771 AC: 1632 AN: 2116

Alfa AF: 0.733 Hom.: 84998

Bravo AF: 0.806

Asia WGS AF: 0.762 AC: 2648 AN: 3478

EpiCase AF: 0.700

EpiControl AF: 0.710

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	9.5
DANN	Benign	0.47
PhyloP100		-0.18
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: rs1376041; hg19: chr16-57689883; COSMIC: COSV65635932; COSMIC: COSV65635932;