rs186479054

Variant names:

• chr16-57656000-G-A
• rs186479054
• NM_201525.4:c.1017+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-57656000-G-A
• chr16-57656000-G-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.1017+8G>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 0.00293 in 1,614,018 control chromosomes in the GnomAD database, including 11 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (10 hom.)
• Consequence: ADGRG1 NM_201525.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001787
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.441
• Publications: 1 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=-0.87).
• BP6: Variant 16-57656000-G-A is Benign according to our data. Variant chr16-57656000-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00303 (4436/1461676) while in subpopulation NFE AF = 0.00339 (3775/1111988). AF 95% confidence interval is 0.0033. There are 10 homozygotes in GnomAdExome4. There are 2145 alleles in the male GnomAdExome4 subpopulation. Median coverage is 39. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.1017+8G>A		splice_region intron	N/A	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001145771.3		c.1017+8G>A		splice_region intron	N/A	NP_001139243.1	Q9Y653-1
	ADGRG1	NM_001370428.1		c.1017+8G>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.1017+8G>A		splice_region intron	N/A	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.1017+8G>A		splice_region intron	N/A	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.1017+8G>A		splice_region intron	N/A	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 297 AN: 152224 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00203 AC: 509 AN: 250926 AF XY: 0.00204

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00775

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00257

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00303 AC: 4436 AN: 1461676 Hom.: 10 Cov.: 39 AF XY: 0.00295 AC XY: 2145 AN XY: 727148

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.00280 AC: 125 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 218 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00143 AC: 76 AN: 53280

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5736

European-Non Finnish (NFE) AF: 0.00339 AC: 3775 AN: 1111988

Other (OTH) AF: 0.00358 AC: 216 AN: 60378

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152342 Hom.: 1 Cov.: 32 AF XY: 0.00153 AC XY: 114 AN XY: 74506

African (AFR) AF: 0.000601 AC: 25 AN: 41582

American (AMR) AF: 0.00216 AC: 33 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00264 Hom.: 0

Bravo AF: 0.00232

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Bilateral frontoparietal polymicrogyria (2)
-	-	1	ADGRG1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.68
DANN	Benign	0.57
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0
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: rs186479054; hg19: chr16-57689912;