15-32718211-G-A

Variant names:

• chr15-32718211-G-A
• rs2293582
• NM_013372.7:c.-2+50G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 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-AS1 (HGNC:55411): (GREM1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-2+50G>A		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1
GREM1-AS1	NR_109767.1	n.475C>T		non_coding_transcript_exon_variant	Exon 2 of 2
GREM1	NM_001191323.2	c.-2+50G>A		intron_variant	Intron 1 of 2		NP_001178252.1
GREM1	NM_001191322.2	c.-2+50G>A		intron_variant	Intron 1 of 2		NP_001178251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+50G>A		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-2+50G>A		intron_variant	Intron 1 of 2	4		ENSP00000453387.1

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

GnomAD2 exomes AF: 0.231 AC: 30164 AN: 130592 AF XY: 0.235

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 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

African (AFR) AF: 0.161 AC: 4241 AN: 26408

American (AMR) AF: 0.186 AC: 5538 AN: 29778

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 2791 AN: 19464

East Asian (EAS) AF: 0.483 AC: 10815 AN: 22396

South Asian (SAS) AF: 0.290 AC: 21880 AN: 75522

European-Finnish (FIN) AF: 0.256 AC: 3268 AN: 12780

Middle Eastern (MID) AF: 0.176 AC: 822 AN: 4672

European-Non Finnish (NFE) AF: 0.196 AC: 179671 AN: 918872

Other (OTH) AF: 0.216 AC: 9710 AN: 44990

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

African (AFR) AF: 0.171 AC: 7093 AN: 41516

American (AMR) AF: 0.182 AC: 2776 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 491 AN: 3466

East Asian (EAS) AF: 0.481 AC: 2451 AN: 5100

South Asian (SAS) AF: 0.303 AC: 1458 AN: 4812

European-Finnish (FIN) AF: 0.260 AC: 2751 AN: 10570

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13254 AN: 67920

Other (OTH) AF: 0.203 AC: 429 AN: 2110

Alfa AF: 0.196 Hom.: 4588

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

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27379672) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.7
DANN	Benign	0.86
PhyloP100		-1.5
PromoterAI		-0.079	Neutral
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: rs2293582; hg19: chr15-33010412; COSMIC: COSV55714438;