rs3743105

Variant names:

• chr15-32731750-T-C
• rs3743105
• NM_013372.7:c.*505T>C

Variant summary

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

The NM_013372.7(GREM1):​c.*505T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.528 in 242,012 control chromosomes in the GnomAD database, including 36,432 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 0.49 (20503 hom., cov: 31)
  • Exomes 𝑓: 0.59 (15929 hom.)
• Consequence: GREM1 NM_013372.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 11 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.*505T>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.*505T>C		3_prime_UTR_variant	Exon 2 of 2		NP_001355648.1
GREM1	NM_001191323.2	c.*505T>C		3_prime_UTR_variant	Exon 3 of 3		NP_001178252.1
GREM1	NM_001191322.2	c.*505T>C		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.*505T>C		3_prime_UTR_variant	Exon 2 of 2		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000652365.1	c.*505T>C		3_prime_UTR_variant	Exon 2 of 2			ENSP00000498763.1
GREM1	ENST00000560830.1	c.*505T>C		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 74993 AN: 151868 Hom.: 20499 Cov.: 31

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.619

Gnomad FIN AF: 0.612

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.583

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.587 AC: 52833 AN: 90026 Hom.: 15929 Cov.: 0 AF XY: 0.592 AC XY: 24903 AN XY: 42060

African (AFR) AF: 0.234 AC: 801 AN: 3430

American (AMR) AF: 0.516 AC: 1396 AN: 2706

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2644 AN: 4516

East Asian (EAS) AF: 0.675 AC: 6899 AN: 10224

South Asian (SAS) AF: 0.587 AC: 465 AN: 792

European-Finnish (FIN) AF: 0.613 AC: 9135 AN: 14890

Middle Eastern (MID) AF: 0.554 AC: 236 AN: 426

European-Non Finnish (NFE) AF: 0.593 AC: 27735 AN: 46802

Other (OTH) AF: 0.564 AC: 3522 AN: 6240

GnomAD4 genome AF: 0.494 AC: 75014 AN: 151986 Hom.: 20503 Cov.: 31 AF XY: 0.500 AC XY: 37168 AN XY: 74266

African (AFR) AF: 0.244 AC: 10122 AN: 41464

American (AMR) AF: 0.528 AC: 8058 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2104 AN: 3472

East Asian (EAS) AF: 0.768 AC: 3964 AN: 5160

South Asian (SAS) AF: 0.621 AC: 2983 AN: 4800

European-Finnish (FIN) AF: 0.612 AC: 6454 AN: 10548

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.583 AC: 39642 AN: 67962

Other (OTH) AF: 0.521 AC: 1100 AN: 2112

Alfa AF: 0.551 Hom.: 45611

Bravo AF: 0.476

Asia WGS AF: 0.638 AC: 2220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	7.0
DANN	Benign	0.59
PhyloP100		1.1
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: rs3743105; hg19: chr15-33023951;