16-57659696-G-C

Variant names:

• chr16-57659696-G-C
• rs75843478
• NM_201525.4:c.1555+15G>C

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.1555+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,611,888 control chromosomes in the GnomAD database, including 1,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (143 hom., cov: 32)
  • Exomes 𝑓: 0.013 (1130 hom.)
• Consequence: ADGRG1 NM_201525.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.259
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-57659696-G-C is Benign according to our data. Variant chr16-57659696-G-C is described in ClinVar as Benign. ClinVar VariationId is 137496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	NM_201525.4	MANE Select	c.1555+15G>C		intron	N/A	NP_958933.1
	ADGRG1	NM_001145771.3		c.1573+15G>C		intron	N/A	NP_001139243.1
	ADGRG1	NM_001370428.1		c.1573+15G>C		intron	N/A	NP_001357357.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.1555+15G>C		intron	N/A	ENSP00000455351.2
	ADGRG1	ENST00000567835.5	TSL:1	c.1573+15G>C		intron	N/A	ENSP00000456794.1
	ADGRG1	ENST00000388813.9	TSL:1	c.1555+15G>C		intron	N/A	ENSP00000373465.5

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2632 AN: 152084 Hom.: 142 Cov.: 32

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.0736

Gnomad FIN AF: 0.0302

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00241

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0354 AC: 8687 AN: 245728 AF XY: 0.0348

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0558

Gnomad ASJ exome AF: 0.00341

Gnomad EAS exome AF: 0.200

Gnomad FIN exome AF: 0.0270

Gnomad NFE exome AF: 0.00236

Gnomad OTH exome AF: 0.0283

GnomAD4 exome AF: 0.0135 AC: 19663 AN: 1459684 Hom.: 1130 Cov.: 35 AF XY: 0.0148 AC XY: 10735 AN XY: 726100

African (AFR) AF: 0.00141 AC: 47 AN: 33450

American (AMR) AF: 0.0544 AC: 2431 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 83 AN: 26126

East Asian (EAS) AF: 0.187 AC: 7431 AN: 39686

South Asian (SAS) AF: 0.0616 AC: 5314 AN: 86216

European-Finnish (FIN) AF: 0.0255 AC: 1342 AN: 52588

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5760

European-Non Finnish (NFE) AF: 0.00161 AC: 1783 AN: 1110842

Other (OTH) AF: 0.0199 AC: 1203 AN: 60312

GnomAD4 genome AF: 0.0174 AC: 2643 AN: 152204 Hom.: 143 Cov.: 32 AF XY: 0.0213 AC XY: 1587 AN XY: 74418

African (AFR) AF: 0.00195 AC: 81 AN: 41536

American (AMR) AF: 0.0429 AC: 655 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

East Asian (EAS) AF: 0.196 AC: 1012 AN: 5164

South Asian (SAS) AF: 0.0739 AC: 356 AN: 4820

European-Finnish (FIN) AF: 0.0302 AC: 320 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00241 AC: 164 AN: 68010

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.00408 Hom.: 2

Bravo AF: 0.0171

Asia WGS AF: 0.145 AC: 505 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.34
PhyloP100		-0.26
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: rs75843478; hg19: chr16-57693608; COSMIC: COSV65636385;