rs12915554

Positions:

• chr15-32731285-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: 0.580

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 -14 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 id is 1282623.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.*40C>A		3_prime_UTR_variant	2/2	ENST00000651154.1
GREM1	NM_001191322.2	c.*40C>A		3_prime_UTR_variant	3/3
GREM1	NM_001191323.2	c.*40C>A		3_prime_UTR_variant	3/3
GREM1	NM_001368719.1	c.*40C>A		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.*40C>A		3_prime_UTR_variant	2/2		NM_013372.7	P1
GREM1	ENST00000560830.1	c.*40C>A		3_prime_UTR_variant	3/3	2
GREM1	ENST00000652365.1	c.*40C>A		3_prime_UTR_variant	2/2			P1
GREM1	ENST00000560677.5			downstream_gene_variant		4

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

GnomAD3 exomes AF: 0.288 AC: 63702 AN: 221372 Hom.: 10275 AF XY: 0.293 AC XY: 34644 AN XY: 118134

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 SAS exome AF: 0.235

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

Gnomad4 AFR exome AF: 0.0929

Gnomad4 AMR exome AF: 0.307

Gnomad4 ASJ exome AF: 0.377

Gnomad4 EAS exome AF: 0.0230

Gnomad4 SAS exome AF: 0.238

Gnomad4 FIN exome AF: 0.294

Gnomad4 NFE exome AF: 0.356

Gnomad4 OTH exome AF: 0.317

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

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.314

Gnomad4 ASJ AF: 0.394

Gnomad4 EAS AF: 0.0293

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.358

Gnomad4 OTH AF: 0.276

Alfa AF: 0.341 Hom.: 14392

Bravo AF: 0.258

Asia WGS AF: 0.124 AC: 437 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

This variant is associated with the following publications: (PMID: 28977865) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.7
DANN	Benign	0.73

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: rs12915554; hg19: chr15-33023486; COSMIC: COSV55715058; COSMIC: COSV55715058;