15-32731784-A-G

Variant names:

• chr15-32731784-A-G
• rs3743104
• NM_013372.7:c.*539A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 18 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, Orphanet, G2P
• polyposis syndrome, hereditary mixed, 1

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

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.*539A>G		3_prime_UTR_variant	Exon 2 of 2	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.*539A>G		3_prime_UTR_variant	Exon 2 of 2		NP_001355648.1
GREM1	NM_001191323.2	c.*539A>G		3_prime_UTR_variant	Exon 3 of 3		NP_001178252.1
GREM1	NM_001191322.2	c.*539A>G		3_prime_UTR_variant	Exon 3 of 3		NP_001178251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.*539A>G		3_prime_UTR_variant	Exon 2 of 2		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000652365.1	c.*539A>G		3_prime_UTR_variant	Exon 2 of 2			ENSP00000498763.1
GREM1	ENST00000560830.1	c.*539A>G		3_prime_UTR_variant	Exon 3 of 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

African (AFR) AF: 0.233 AC: 748 AN: 3204

American (AMR) AF: 0.522 AC: 1113 AN: 2132

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 2436 AN: 4338

East Asian (EAS) AF: 0.503 AC: 4975 AN: 9886

South Asian (SAS) AF: 0.505 AC: 316 AN: 626

European-Finnish (FIN) AF: 0.569 AC: 8406 AN: 14780

Middle Eastern (MID) AF: 0.529 AC: 218 AN: 412

European-Non Finnish (NFE) AF: 0.587 AC: 25123 AN: 42834

Other (OTH) AF: 0.545 AC: 3217 AN: 5900

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

African (AFR) AF: 0.243 AC: 10045 AN: 41404

American (AMR) AF: 0.521 AC: 7949 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2029 AN: 3470

East Asian (EAS) AF: 0.551 AC: 2833 AN: 5140

South Asian (SAS) AF: 0.543 AC: 2606 AN: 4802

European-Finnish (FIN) AF: 0.574 AC: 6051 AN: 10544

Middle Eastern (MID) AF: 0.575 AC: 169 AN: 294

European-Non Finnish (NFE) AF: 0.576 AC: 39127 AN: 67952

Other (OTH) AF: 0.503 AC: 1063 AN: 2114

Alfa AF: 0.539 Hom.: 93747

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
PhyloP100		-0.21
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: rs3743104; hg19: chr15-33023985;