rs2280738

Positions:

• chr15-32730897-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013372.7(GREM1):​c.207C>G​(p.Pro69=) 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:4
• Conservation: PhyloP100: -9.53

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
GREM1	NM_013372.7	c.207C>G	p.Pro69=	synonymous_variant	2/2	ENST00000651154.1
GREM1	NM_001368719.1	c.207C>G	p.Pro69=	synonymous_variant	2/2
GREM1	NM_001191322.2	c.28-31C>G		intron_variant
GREM1	NM_001191323.2	c.115-31C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.207C>G	p.Pro69=	synonymous_variant	2/2		NM_013372.7	P1
GREM1	ENST00000652365.1	c.207C>G	p.Pro69=	synonymous_variant	2/2			P1
GREM1	ENST00000560677.5	c.105-19C>G		intron_variant		4
GREM1	ENST00000560830.1	c.115-31C>G		intron_variant		2

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

GnomAD3 exomes AF: 0.0358 AC: 8891 AN: 248442 Hom.: 562 AF XY: 0.0373 AC XY: 5033 AN XY: 134790

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 SAS exome AF: 0.0784

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

Gnomad4 AFR exome AF: 0.0157

Gnomad4 AMR exome AF: 0.00772

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.180

Gnomad4 SAS exome AF: 0.0782

Gnomad4 FIN exome AF: 0.0383

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.0287

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

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.0786

Gnomad4 FIN AF: 0.0382

Gnomad4 NFE AF: 0.00756

Gnomad4 OTH AF: 0.0242

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0030
DANN	Benign	0.73
BranchPoint Hunter		1.0

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

Other links and lift over

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