rs74326170

Variant names:

• chr16-57657497-G-A
• rs74326170
• NM_201525.4:c.1286+6G>A

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.1286+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,604,548 control chromosomes in the GnomAD database, including 1,218 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (524 hom., cov: 32)
  • Exomes 𝑓: 0.012 (694 hom.)
• Consequence: ADGRG1 NM_201525.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003660
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.224
• Publications: 2 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 (BayesDel_noAF=-0.75).
• BP6: Variant 16-57657497-G-A is Benign according to our data. Variant chr16-57657497-G-A is described in ClinVar as Benign. ClinVar VariationId is 137494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 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.1286+6G>A		splice_region intron	N/A	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.1286+6G>A		splice_region intron	N/A	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.1286+6G>A		splice_region intron	N/A	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.1286+6G>A		splice_region intron	N/A	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.1286+6G>A		splice_region intron	N/A	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.1286+6G>A		splice_region intron	N/A	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes AF: 0.0515 AC: 7831 AN: 152138 Hom.: 520 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0228

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0863

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00576

Gnomad OTH AF: 0.0526

GnomAD2 exomes AF: 0.0246 AC: 6172 AN: 251082 AF XY: 0.0219

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.0894

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.00585

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0123 AC: 17871 AN: 1452292 Hom.: 694 Cov.: 29 AF XY: 0.0120 AC XY: 8670 AN XY: 722976

African (AFR) AF: 0.164 AC: 5457 AN: 33260

American (AMR) AF: 0.0176 AC: 787 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 283 AN: 26064

East Asian (EAS) AF: 0.0709 AC: 2809 AN: 39640

South Asian (SAS) AF: 0.0170 AC: 1465 AN: 86088

European-Finnish (FIN) AF: 0.000642 AC: 34 AN: 52998

Middle Eastern (MID) AF: 0.0321 AC: 184 AN: 5736

European-Non Finnish (NFE) AF: 0.00480 AC: 5294 AN: 1103744

Other (OTH) AF: 0.0259 AC: 1558 AN: 60054

GnomAD4 genome AF: 0.0516 AC: 7859 AN: 152256 Hom.: 524 Cov.: 32 AF XY: 0.0506 AC XY: 3766 AN XY: 74450

African (AFR) AF: 0.154 AC: 6407 AN: 41528

American (AMR) AF: 0.0227 AC: 348 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.0859 AC: 444 AN: 5166

South Asian (SAS) AF: 0.0203 AC: 98 AN: 4824

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.00575 AC: 391 AN: 68024

Other (OTH) AF: 0.0549 AC: 116 AN: 2112

Alfa AF: 0.0237 Hom.: 469

Bravo AF: 0.0595

Asia WGS AF: 0.0610 AC: 213 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00765

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Bilateral frontoparietal polymicrogyria (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.78
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00037
dbscSNV1_RF	Benign	0.040
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: rs74326170; hg19: chr16-57691409;