15-32731784-A-G

Position:

• chr15-32731784-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013372.7(GREM1):​c.*539A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 235,998 control chromosomes in the GnomAD database, including 32,061 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.48 (18840 hom., cov: 31)
  • Exomes 𝑓: 0.55 (13221 hom.)
• Consequence: GREM1 NM_013372.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.208

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREM1	NM_013372.7	c.*539A>G		3_prime_UTR_variant	2/2	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.*539A>G		3_prime_UTR_variant	2/2		NP_001355648.1
GREM1	NM_001191323.2	c.*539A>G		3_prime_UTR_variant	3/3		NP_001178252.1
GREM1	NM_001191322.2	c.*539A>G		3_prime_UTR_variant	3/3		NP_001178251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.*539A>G		3_prime_UTR_variant	2/2		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000652365.1	c.*539A>G		3_prime_UTR_variant	2/2			ENSP00000498763.1
GREM1	ENST00000560830.1	c.*539A>G		3_prime_UTR_variant	3/3	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72269 AN: 151768 Hom.: 18836 Cov.: 31

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.541

Gnomad FIN AF: 0.574

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.576

Gnomad OTH AF: 0.499

GnomAD4 exome AF: 0.553 AC: 46552 AN: 84112 Hom.: 13221 Cov.: 0 AF XY: 0.559 AC XY: 21867 AN XY: 39138

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.522

Gnomad4 ASJ exome AF: 0.562

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.505

Gnomad4 FIN exome AF: 0.569

Gnomad4 NFE exome AF: 0.587

Gnomad4 OTH exome AF: 0.545

GnomAD4 genome AF: 0.476 AC: 72289 AN: 151886 Hom.: 18840 Cov.: 31 AF XY: 0.480 AC XY: 35596 AN XY: 74226

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.521

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.543

Gnomad4 FIN AF: 0.574

Gnomad4 NFE AF: 0.576

Gnomad4 OTH AF: 0.503

Alfa AF: 0.556 Hom.: 41973

Bravo AF: 0.461

Asia WGS AF: 0.512 AC: 1784 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.8
DANN	Benign	0.89

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: rs3743104; hg19: chr15-33023985;