rs1129456

Variant names:

• chr15-32734466-A-T
• rs1129456
• NM_013372.7:c.*3221A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013372.7(GREM1):​c.*3221A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 246,262 control chromosomes in the GnomAD database, including 4,520 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 0.18 (3512 hom., cov: 33)
  • Exomes 𝑓: 0.13 (1008 hom.)
• Consequence: GREM1 NM_013372.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.385
• Publications: 16 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=-0.62).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.*3221A>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.*3221A>T		3_prime_UTR_variant	Exon 2 of 2		NP_001355648.1
GREM1	NM_001191323.2	c.*3221A>T		3_prime_UTR_variant	Exon 3 of 3		NP_001178252.1
GREM1	NM_001191322.2	c.*3221A>T		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.*3221A>T		3_prime_UTR_variant	Exon 2 of 2		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000652365.1	c.*3221A>T		3_prime_UTR_variant	Exon 2 of 2			ENSP00000498763.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28019 AN: 152080 Hom.: 3480 Cov.: 33

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0896

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.134 AC: 12575 AN: 94064 Hom.: 1008 Cov.: 0 AF XY: 0.131 AC XY: 5723 AN XY: 43554

African (AFR) AF: 0.359 AC: 1367 AN: 3804

American (AMR) AF: 0.0976 AC: 240 AN: 2458

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 495 AN: 5008

East Asian (EAS) AF: 0.159 AC: 1759 AN: 11088

South Asian (SAS) AF: 0.147 AC: 102 AN: 694

European-Finnish (FIN) AF: 0.137 AC: 2014 AN: 14734

Middle Eastern (MID) AF: 0.115 AC: 55 AN: 480

European-Non Finnish (NFE) AF: 0.113 AC: 5554 AN: 49076

Other (OTH) AF: 0.147 AC: 989 AN: 6722

GnomAD4 genome AF: 0.185 AC: 28106 AN: 152198 Hom.: 3512 Cov.: 33 AF XY: 0.184 AC XY: 13687 AN XY: 74424

African (AFR) AF: 0.354 AC: 14677 AN: 41482

American (AMR) AF: 0.110 AC: 1684 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0896 AC: 311 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1087 AN: 5178

South Asian (SAS) AF: 0.139 AC: 673 AN: 4830

European-Finnish (FIN) AF: 0.133 AC: 1409 AN: 10604

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7816 AN: 68010

Other (OTH) AF: 0.174 AC: 369 AN: 2116

Alfa AF: 0.155 Hom.: 304

Bravo AF: 0.191

Asia WGS AF: 0.174 AC: 606 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.9
DANN	Benign	0.81
PhyloP100		0.39
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: rs1129456; hg19: chr15-33026667;