16-57654006-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000562631.7(ADGRG1):​c.641C>T​(p.Ser214Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,614,066 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S214W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 32)
Exomes 𝑓: 0.00033 ( 6 hom. )

Consequence

ADGRG1
ENST00000562631.7 missense

Scores

3
14

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.871
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.007232785).
BP6
Variant 16-57654006-C-T is Benign according to our data. Variant chr16-57654006-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 265187.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 = 0.00328 (499/152294) while in subpopulation AFR AF= 0.0116 (484/41566). AF 95% confidence interval is 0.0108. There are 4 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ADGRG1NM_201525.4 linkuse as main transcriptc.641C>T p.Ser214Leu missense_variant 5/14 ENST00000562631.7 NP_958933.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ADGRG1ENST00000562631.7 linkuse as main transcriptc.641C>T p.Ser214Leu missense_variant 5/141 NM_201525.4 ENSP00000455351 P4Q9Y653-2

Frequencies

GnomAD3 genomes
AF:
0.00328
AC:
499
AN:
152176
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0117
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000392
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.000827
AC:
208
AN:
251416
Hom.:
0
AF XY:
0.000640
AC XY:
87
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.0119
Gnomad AMR exome
AF:
0.000231
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:
0.0000440
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000331
AC:
484
AN:
1461772
Hom.:
6
Cov.:
34
AF XY:
0.000265
AC XY:
193
AN XY:
727180
show subpopulations
Gnomad4 AFR exome
AF:
0.0126
Gnomad4 AMR exome
AF:
0.000291
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:
0.0000144
Gnomad4 OTH exome
AF:
0.000530
GnomAD4 genome
AF:
0.00328
AC:
499
AN:
152294
Hom.:
4
Cov.:
32
AF XY:
0.00321
AC XY:
239
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.0116
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00100
Hom.:
1
Bravo
AF:
0.00345
ESP6500AA
AF:
0.0105
AC:
46
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000964
AC:
117
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 06, 2020- -
Likely benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 22, 2017- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Bilateral frontoparietal polymicrogyria Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria providedclinical testingNatera, Inc.Oct 18, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.17
.;T;T;T;.;.;.;.;.
Eigen
Benign
-0.015
Eigen_PC
Benign
-0.049
FATHMM_MKL
Benign
0.64
D
LIST_S2
Uncertain
0.90
.;.;D;D;.;D;.;.;D
MetaRNN
Benign
0.0072
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
0.97
N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.4
N;N;D;N;N;.;N;N;N
REVEL
Benign
0.14
Sift
Benign
0.11
T;T;D;T;T;.;T;T;T
Sift4G
Benign
0.37
T;T;D;T;T;T;T;T;T
Polyphen
0.21
B;D;.;D;B;.;B;B;B
Vest4
0.50
MVP
0.96
ClinPred
0.014
T
GERP RS
4.0
Varity_R
0.076
gMVP
0.40

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs114515505; hg19: chr16-57687918; COSMIC: COSV65635772; COSMIC: COSV65635772; API