rs113005540

Variant names:

• chr16-57653219-C-T
• rs113005540
• NM_201525.4:c.504C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001290143.2(ADGRG1):​c.-22C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000898 in 1,610,556 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: ADGRG1 NM_001290143.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.334
• 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=-0.74).
• BP6: Variant 16-57653219-C-T is Benign according to our data. Variant chr16-57653219-C-T is described in ClinVar as Benign. ClinVar VariationId is 158632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00472 (719/152248) while in subpopulation AFR AF = 0.0165 (684/41550). AF 95% confidence interval is 0.0154. There are 7 homozygotes in GnomAd4. There are 342 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290143.2. 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.504C>T	p.Ala168Ala	synonymous	Exon 4 of 14	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001290143.2		c.-22C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 14	NP_001277072.1	Q9Y653-5
	ADGRG1	NM_001290144.2		c.-22C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 14	NP_001277073.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.504C>T	p.Ala168Ala	synonymous	Exon 4 of 14	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.504C>T	p.Ala168Ala	synonymous	Exon 5 of 15	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.504C>T	p.Ala168Ala	synonymous	Exon 5 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 717 AN: 152130 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00124 AC: 306 AN: 246344 AF XY: 0.000912

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000499 AC: 728 AN: 1458308 Hom.: 4 Cov.: 33 AF XY: 0.000458 AC XY: 332 AN XY: 725664

African (AFR) AF: 0.0183 AC: 612 AN: 33476

American (AMR) AF: 0.000447 AC: 20 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50008

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111922

Other (OTH) AF: 0.00129 AC: 78 AN: 60354

GnomAD4 genome AF: 0.00472 AC: 719 AN: 152248 Hom.: 7 Cov.: 33 AF XY: 0.00459 AC XY: 342 AN XY: 74432

African (AFR) AF: 0.0165 AC: 684 AN: 41550

American (AMR) AF: 0.00176 AC: 27 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00165 Hom.: 1

Bravo AF: 0.00570

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.1
DANN	Benign	0.62
PhyloP100		-0.33
PromoterAI		0.0013	Neutral
Mutation Taster		=299/1	polymorphism

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: rs113005540; hg19: chr16-57687131; COSMIC: COSV65635709; COSMIC: COSV65635709;