16-57651400-C-T

Variant names:

• chr16-57651400-C-T
• rs587783658
• NM_201525.4:c.265C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_201525.4(ADGRG1):​c.265C>T​(p.His89Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ADGRG1 NM_201525.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-57651400-C-T is Pathogenic according to our data. 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. Variant chr16-57651400-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRG1	NM_201525.4	c.265C>T	p.His89Tyr	missense_variant	Exon 3 of 14	ENST00000562631.7	NP_958933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRG1	ENST00000562631.7	c.265C>T	p.His89Tyr	missense_variant	Exon 3 of 14	1	NM_201525.4	ENSP00000455351.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000244 Hom.: 0

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bilateral frontoparietal polymicrogyria Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;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	0.91	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	0.17	D
MetaRNN	Uncertain	0.47	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	-0.57	T
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.3	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	0.0070	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	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;D;D
Polyphen		1.0, 1.0	.;D;D;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;D;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.43, 0.44, 0.44, 0.44, 0.44, 0.44, 0.45
MutPred		0.45		Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);.;Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);.;.;Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);.;Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);.;.;.;Loss of disorder (P = 0.0851);.;.;.;Loss of disorder (P = 0.0851);.;.;Loss of disorder (P = 0.0851);.;Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);.;Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);Loss of disorder (P = 0.0851);
MVP		0.98
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs587783658; hg19: chr16-57685312;