rs12915554

Variant names:

• chr15-32731285-C-A
• rs12915554
• NM_013372.7:c.*40C>A

Your query was ambiguous. Multiple possible variants found:

• chr15-32731285-C-A
• chr15-32731285-C-G

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.*40C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.322 in 1,505,728 control chromosomes in the GnomAD database, including 83,511 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6387 hom., cov: 31)
  • Exomes 𝑓: 0.33 (77124 hom.)
• Consequence: GREM1 NM_013372.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.580
• Publications: 25 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, G2P, Orphanet
• polyposis syndrome, hereditary mixed, 1

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 15-32731285-C-A is Benign according to our data. Variant chr15-32731285-C-A is described in ClinVar as Benign. ClinVar VariationId is 1282623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	NM_013372.7	MANE Select	c.*40C>A		3_prime_UTR	Exon 2 of 2	NP_037504.1	A6XAA7
	GREM1	NM_001368719.1		c.*40C>A		3_prime_UTR	Exon 2 of 2	NP_001355648.1	O60565-1
	GREM1	NM_001191323.2		c.*40C>A		3_prime_UTR	Exon 3 of 3	NP_001178252.1	O60565-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	ENST00000651154.1	MANE Select	c.*40C>A		3_prime_UTR	Exon 2 of 2	ENSP00000498748.1	O60565-1
	GREM1	ENST00000652365.1		c.*40C>A		3_prime_UTR	Exon 2 of 2	ENSP00000498763.1	O60565-1
	GREM1	ENST00000908783.1		c.*40C>A		3_prime_UTR	Exon 2 of 2	ENSP00000578842.1

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40125 AN: 151932 Hom.: 6384 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.313

Gnomad ASJ AF: 0.394

Gnomad EAS AF: 0.0292

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.288 AC: 63702 AN: 221372 AF XY: 0.293

Gnomad AFR exome AF: 0.0981

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.387

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.294

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.328 AC: 444298 AN: 1353676 Hom.: 77124 Cov.: 20 AF XY: 0.327 AC XY: 220263 AN XY: 673456

African (AFR) AF: 0.0929 AC: 2902 AN: 31230

American (AMR) AF: 0.307 AC: 12906 AN: 42034

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 8746 AN: 23194

East Asian (EAS) AF: 0.0230 AC: 898 AN: 39086

South Asian (SAS) AF: 0.238 AC: 18577 AN: 77982

European-Finnish (FIN) AF: 0.294 AC: 15290 AN: 51960

Middle Eastern (MID) AF: 0.335 AC: 1818 AN: 5432

European-Non Finnish (NFE) AF: 0.356 AC: 365263 AN: 1026230

Other (OTH) AF: 0.317 AC: 17898 AN: 56528

GnomAD4 genome AF: 0.264 AC: 40135 AN: 152052 Hom.: 6387 Cov.: 31 AF XY: 0.262 AC XY: 19507 AN XY: 74320

African (AFR) AF: 0.103 AC: 4288 AN: 41494

American (AMR) AF: 0.314 AC: 4792 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 1366 AN: 3468

East Asian (EAS) AF: 0.0293 AC: 151 AN: 5158

South Asian (SAS) AF: 0.239 AC: 1147 AN: 4806

European-Finnish (FIN) AF: 0.286 AC: 3020 AN: 10568

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24350 AN: 67954

Other (OTH) AF: 0.276 AC: 584 AN: 2114

Alfa AF: 0.334 Hom.: 18901

Bravo AF: 0.258

Asia WGS AF: 0.124 AC: 437 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.7
DANN	Benign	0.73
PhyloP100		0.58
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: rs12915554; hg19: chr15-33023486; COSMIC: COSV55715058; COSMIC: COSV55715058;