rs587783658

Positions:

• chr16-57651400-C-A
• chr16-57651400-C-G
• chr16-57651400-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The ENST00000562631.7(ADGRG1):​c.265C>A​(p.His89Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADGRG1 ENST00000562631.7 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000562631.7
• 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 ClinVar as [Pathogenic]. Clinvar id is 158628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.41895446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.265C>A	p.His89Asn	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>A	p.His89Asn	missense_variant	3/14	1	NM_201525.4	ENSP00000455351	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000244 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;.;T;T;T;T;.;T;.;.;.;.;T;.;.;T;T;.;.;.;.;T;.;.;.;T;.;.;.;T;T;.;T;.;T;.;T;T;T;T;T;T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	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	Benign	0.42	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	-0.72	T
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	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	0.15
Sift	Uncertain	0.020	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	0.069	T;T;T;D;D;T;D;D;T;T;D;D;T;T;T;D;D;T;D;T;T;T;T;D;D;D;D;T;D;D;D;T;D;D;D;D;T;T;D;T;T;D;D;T
Polyphen		0.99, 0.98	.;D;D;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.49, 0.49, 0.49, 0.49, 0.48, 0.49
MutPred		0.37		Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;.;.;Gain of MoRF binding (P = 0.1028);.;.;.;Gain of MoRF binding (P = 0.1028);.;.;Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);.;Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);Gain of MoRF binding (P = 0.1028);
MVP		0.97
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.15
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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;