Genetic Variant ADGRG1:p.Pro204Pro (chr16-57653327-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_201525.4(ADGRG1):c.612C>T(p.Pro204Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,609,364 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 3 hom. )

Consequence

ADGRG1
NM_201525.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: -2.45

Publications

0 publications found

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]

ADGRG1 Gene-Disease associations (from GenCC):

bilateral frontoparietal polymicrogyria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ADGRG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 16-57653327-C-T is Benign according to our data. Variant chr16-57653327-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158633.

BP7

Synonymous conserved (PhyloP=-2.45 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRG1	NM_201525.4	MANE Select	c.612C>T	p.Pro204Pro	synonymous	Exon 4 of 14	NP_958933.1	Q9Y653-2
ADGRG1	NM_001145771.3		c.612C>T	p.Pro204Pro	synonymous	Exon 5 of 15	NP_001139243.1	Q9Y653-1
ADGRG1	NM_001370428.1		c.612C>T	p.Pro204Pro	synonymous	Exon 5 of 15	NP_001357357.1	Q9Y653-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADGRG1	ENST00000562631.7	TSL:1 MANE Select	c.612C>T	p.Pro204Pro	synonymous	Exon 4 of 14	ENSP00000455351.2	Q9Y653-2
ADGRG1	ENST00000567835.5	TSL:1	c.612C>T	p.Pro204Pro	synonymous	Exon 5 of 15	ENSP00000456794.1	Q9Y653-1
ADGRG1	ENST00000388813.9	TSL:1	c.612C>T	p.Pro204Pro	synonymous	Exon 5 of 15	ENSP00000373465.5	Q9Y653-2

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000884

AC:

214

AN:

242002

AF XY:

0.000862

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.00755

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000172

Gnomad NFE exome

AF:

0.000752

Gnomad OTH exome

AF:

0.000503

GnomAD4 exome

AF:

0.000688

AC:

1002

AN:

1457100

Hom.:

Cov.:

AF XY:

0.000699

AC XY:

507

AN XY:

725086

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33474

American (AMR)

AF:

0.00119

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00700

AC:

183

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39690

South Asian (SAS)

AF:

0.000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.000204

AC:

AN:

48968

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000628

AC:

698

AN:

1111874

Other (OTH)

AF:

0.000630

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000499

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41554

American (AMR)

AF:

0.000718

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68012

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000589

EpiCase

AF:

0.000927

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bilateral frontoparietal polymicrogyria (3)

not provided (3)

ADGRG1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.2

(source)

DANN

Benign

0.46

PhyloP100

-2.4

PromoterAI

-0.025

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over