dbSNP rs2280738: GREM1:p.Pro69Pro (chr15-32730897-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_013372.7(GREM1):c.207C>G(p.Pro69Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,613,540 control chromosomes in the GnomAD database, including 1,320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P69P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 164 hom., cov: 32)

Exomes 𝑓: 0.018 ( 1156 hom. )

Consequence

GREM1
NM_013372.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -9.53

Publications

12 publications found

Variant links:

Genes affected

GREM1 (HGNC:2001): (gremlin 1, DAN family BMP antagonist) This gene encodes a member of the BMP (bone morphogenic protein) antagonist family. Like BMPs, BMP antagonists contain cystine knots and typically form homo- and heterodimers. The CAN (cerberus and dan) subfamily of BMP antagonists, to which this gene belongs, is characterized by a C-terminal cystine knot with an eight-membered ring. The antagonistic effect of the secreted glycosylated protein encoded by this gene is likely due to its direct binding to BMP proteins. As an antagonist of BMP, this gene may play a role in regulating organogenesis, body patterning, and tissue differentiation. In mouse, this protein has been shown to relay the sonic hedgehog (SHH) signal from the polarizing region to the apical ectodermal ridge during limb bud outgrowth. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

GREM1 Gene-Disease associations (from GenCC):

hereditary mixed polyposis syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
polyposis syndrome, hereditary mixed, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

GREM1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_013372.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BP6

Variant 15-32730897-C-G is Benign according to our data. Variant chr15-32730897-C-G is described in ClinVar as Benign. ClinVar VariationId is 402911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-9.53 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013372.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GREM1	NM_013372.7	MANE Select	c.207C>G	p.Pro69Pro	synonymous	Exon 2 of 2	NP_037504.1	A6XAA7
GREM1	NM_001368719.1		c.207C>G	p.Pro69Pro	synonymous	Exon 2 of 2	NP_001355648.1	O60565-1
GREM1	NM_001191323.2		c.115-31C>G		intron	N/A	NP_001178252.1	O60565-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GREM1	ENST00000651154.1	MANE Select	c.207C>G	p.Pro69Pro	synonymous	Exon 2 of 2	ENSP00000498748.1	O60565-1
GREM1	ENST00000560677.5	TSL:4	c.105-19C>G		intron	N/A	ENSP00000453387.1	H0YLY2
GREM1	ENST00000652365.1		c.207C>G	p.Pro69Pro	synonymous	Exon 2 of 2	ENSP00000498763.1	O60565-1

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3279

AN:

152076

Hom.:

164

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.215

Gnomad SAS

AF:

0.0781

Gnomad FIN

AF:

0.0382

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00756

Gnomad OTH

AF:

0.0230

GnomAD2 exomes

AF:

0.0358

AC:

8891

AN:

248442

AF XY:

0.0373

show subpopulations

Gnomad AFR exome

AF:

0.0153

Gnomad AMR exome

AF:

0.00719

Gnomad ASJ exome

AF:

0.0261

Gnomad EAS exome

AF:

0.211

Gnomad FIN exome

AF:

0.0402

Gnomad NFE exome

AF:

0.00759

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0183

AC:

26674

AN:

1461346

Hom.:

1156

Cov.:

AF XY:

0.0200

AC XY:

14530

AN XY:

726928

show subpopulations

African (AFR)

AF:

0.0157

AC:

527

AN:

33480

American (AMR)

AF:

0.00772

AC:

345

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0241

AC:

630

AN:

26104

East Asian (EAS)

AF:

0.180

AC:

7158

AN:

39700

South Asian (SAS)

AF:

0.0782

AC:

6738

AN:

86206

European-Finnish (FIN)

AF:

0.0383

AC:

2037

AN:

53188

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00667

AC:

7419

AN:

1111820

Other (OTH)

AF:

0.0287

AC:

1734

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1572

3144

4717

6289

7861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.0216

AC:

3295

AN:

152194

Hom.:

164

Cov.:

AF XY:

0.0246

AC XY:

1832

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0151

AC:

628

AN:

41538

American (AMR)

AF:

0.00863

AC:

132

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3472

East Asian (EAS)

AF:

0.215

AC:

1105

AN:

5150

South Asian (SAS)

AF:

0.0786

AC:

379

AN:

4822

European-Finnish (FIN)

AF:

0.0382

AC:

405

AN:

10602

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00756

AC:

514

AN:

68008

Other (OTH)

AF:

0.0242

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

154

309

463

618

772

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0121

Hom.:

Bravo

AF:

0.0193

Asia WGS

AF:

0.126

AC:

439

AN:

3478

EpiCase

AF:

0.00736

EpiControl

AF:

0.00693

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (2)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.0030

(source)

DANN

Benign

0.73

PhyloP100

-9.5

BranchPoint Hunter

1.0

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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