rs2280738

Variant names:

• chr15-32730897-C-G
• rs2280738
• NM_013372.7:c.207C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-32730897-C-G
• chr15-32730897-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -9.53
• Publications: 12 publications found

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: ClinGen, Orphanet, G2P
• polyposis syndrome, hereditary mixed, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.207C>G	p.Pro69Pro	synonymous_variant	Exon 2 of 2	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.207C>G	p.Pro69Pro	synonymous_variant	Exon 2 of 2		NP_001355648.1
GREM1	NM_001191323.2	c.115-31C>G		intron_variant	Intron 2 of 2		NP_001178252.1
GREM1	NM_001191322.2	c.28-31C>G		intron_variant	Intron 2 of 2		NP_001178251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.207C>G	p.Pro69Pro	synonymous_variant	Exon 2 of 2		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.105-19C>G		intron_variant	Intron 2 of 2	4		ENSP00000453387.1
GREM1	ENST00000652365.1	c.207C>G	p.Pro69Pro	synonymous_variant	Exon 2 of 2			ENSP00000498763.1
GREM1	ENST00000560830.1	c.115-31C>G		intron_variant	Intron 2 of 2	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3279 AN: 152076 Hom.: 164 Cov.: 32

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

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.: 33 AF XY: 0.0200 AC XY: 14530 AN XY: 726928

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: 86 AN: 5766

European-Non Finnish (NFE) AF: 0.00667 AC: 7419 AN: 1111820

Other (OTH) AF: 0.0287 AC: 1734 AN: 60372

GnomAD4 genome AF: 0.0216 AC: 3295 AN: 152194 Hom.: 164 Cov.: 32 AF XY: 0.0246 AC XY: 1832 AN XY: 74398

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: 77 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: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00756 AC: 514 AN: 68008

Other (OTH) AF: 0.0242 AC: 51 AN: 2108

Alfa AF: 0.0121 Hom.: 13

Bravo AF: 0.0193

Asia WGS AF: 0.126 AC: 439 AN: 3478

EpiCase AF: 0.00736

EpiControl AF: 0.00693

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Jul 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary cancer-predisposing syndrome Benign:1

Dec 23, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The synonymous variant NM_013372.7(GREM1):c.207C>G (p.Pro69=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 402911 as of 2024-12-05). The p.Pro69= variant is not predicted to disrupt an existing splice site. The p.Pro69= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0030
DANN	Benign	0.73
PhyloP100		-9.5
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2280738; hg19: chr15-33023098; COSMIC: COSV55714571;