rs2293582

Positions:

• chr15-32718211-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013372.7(GREM1):​c.-2+50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,306,870 control chromosomes in the GnomAD database, including 29,890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3428 hom., cov: 31)
  • Exomes 𝑓: 0.21 (26462 hom.)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45

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-AS1 (HGNC:55411): (GREM1 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-32718211-G-A is Benign according to our data. Variant chr15-32718211-G-A is described in ClinVar as [Benign]. Clinvar id is 1297801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.465 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.-2+50G>A		intron_variant		ENST00000651154.1
GREM1-AS1	NR_109767.1	n.475C>T		non_coding_transcript_exon_variant	2/2
GREM1	NM_001191322.2	c.-2+50G>A		intron_variant
GREM1	NM_001191323.2	c.-2+50G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+50G>A		intron_variant			NM_013372.7	P1
GREM1-AS1	ENST00000558441.1	n.797C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30825 AN: 151870 Hom.: 3425 Cov.: 31

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.199

GnomAD3 exomes AF: 0.231 AC: 30164 AN: 130592 Hom.: 4086 AF XY: 0.235 AC XY: 16755 AN XY: 71148

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.491

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.207 AC: 238736 AN: 1154882 Hom.: 26462 Cov.: 20 AF XY: 0.209 AC XY: 117973 AN XY: 564472

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.483

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.203 AC: 30839 AN: 151988 Hom.: 3428 Cov.: 31 AF XY: 0.207 AC XY: 15356 AN XY: 74272

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.303

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.195

Gnomad4 OTH AF: 0.203

Alfa AF: 0.191 Hom.: 560

Bravo AF: 0.195

Asia WGS AF: 0.397 AC: 1378 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	This variant is associated with the following publications: (PMID: 27379672) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.86

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: rs2293582; hg19: chr15-33010412; COSMIC: COSV55714438;