16-57651400-C-G

Position:

• chr16-57651400-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_201525.4(ADGRG1):​c.265C>G​(p.His89Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H89Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-57651400-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.265C>G	p.His89Asp	missense_variant	3/14	ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7	c.265C>G	p.His89Asp	missense_variant	3/14	1	NM_201525.4	ENSP00000455351.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;.;T;T;T;T;.;T;.;.;.;.;T;.;.;T;T;.;.;.;.;T;.;.;.;T;.;.;.;T;T;.;T;.;T;.;T;T;T;T;T;T;T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;.;.;D;D;D;D;D;D;D;D;D;.;D;.;D;D;D;.;.;.;D;D;D;D;D;D;D;.;.;D;D;D;D;D;D;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.9	D;N;N;D;D;N;D;D;D;D;D;D;D;D;N;D;D;.;D;N;N;D;D;D;D;D;D;D;.;D;D;N;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.21
Sift	Uncertain	0.019	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.14	T;D;D;D;D;D;D;D;T;T;D;D;T;T;D;D;D;D;D;D;D;T;T;D;D;D;D;T;D;D;D;D;D;D;D;D;T;T;D;T;T;D;D;T
Polyphen		1.0, 1.0	.;D;D;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.54, 0.55, 0.55, 0.54, 0.54
MutPred		0.44		Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);.;Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);.;.;Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);.;Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);.;.;.;Loss of MoRF binding (P = 0.0834);.;.;.;Loss of MoRF binding (P = 0.0834);.;.;Loss of MoRF binding (P = 0.0834);.;Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);.;Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);Loss of MoRF binding (P = 0.0834);
MVP		0.96
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783658; hg19: chr16-57685312;