NM_201525.4:c.174C>G

Variant names:

• chr16-57651309-C-G
• rs140963173
• NM_201525.4:c.174C>G
• ADGRG1 p.Ile58Met

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_201525.4(ADGRG1):​c.174C>G​(p.Ile58Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I58I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0290
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21122897).

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.174C>G	p.Ile58Met	missense	Exon 3 of 14	NP_958933.1	Q9Y653-2
	ADGRG1	NM_001290143.2		c.-352C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 14	NP_001277072.1	Q9Y653-5
	ADGRG1	NM_001290144.2		c.-352C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 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.174C>G	p.Ile58Met	missense	Exon 3 of 14	ENSP00000455351.2	Q9Y653-2
	ADGRG1	ENST00000567835.5	TSL:1	c.174C>G	p.Ile58Met	missense	Exon 4 of 15	ENSP00000456794.1	Q9Y653-1
	ADGRG1	ENST00000388813.9	TSL:1	c.174C>G	p.Ile58Met	missense	Exon 4 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251484 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.74	T
PhyloP100		-0.029
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.20
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs140963173;

hg19: chr16-57685221;