rs35330276

Variant names:

• chr15-32729889-G-A
• rs35330276
• NM_013372.7:c.-1-801G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013372.7(GREM1):​c.-1-801G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.166 in 152,210 control chromosomes in the GnomAD database, including 2,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (2832 hom., cov: 33)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.116
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-32729889-G-A is Benign according to our data. Variant chr15-32729889-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288795.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-1-801G>A		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.-1-801G>A		intron_variant	Intron 1 of 1		NP_001355648.1
GREM1	NM_001191323.2	c.-1-801G>A		intron_variant	Intron 1 of 2		NP_001178252.1
GREM1	NM_001191322.2	c.-1-801G>A		intron_variant	Intron 1 of 2		NP_001178251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.-1-801G>A		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-1-801G>A		intron_variant	Intron 1 of 2	4		ENSP00000453387.1
GREM1	ENST00000652365.1	c.-1-801G>A		intron_variant	Intron 1 of 1			ENSP00000498763.1
GREM1	ENST00000560830.1	c.-1-801G>A		intron_variant	Intron 1 of 2	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25210 AN: 152092 Hom.: 2831 Cov.: 33

Gnomad AFR AF: 0.0463

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.175

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.166 AC: 25213 AN: 152210 Hom.: 2832 Cov.: 33 AF XY: 0.172 AC XY: 12773 AN XY: 74410

African (AFR) AF: 0.0463 AC: 1923 AN: 41556

American (AMR) AF: 0.173 AC: 2638 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 456 AN: 3472

East Asian (EAS) AF: 0.523 AC: 2711 AN: 5186

South Asian (SAS) AF: 0.299 AC: 1442 AN: 4826

European-Finnish (FIN) AF: 0.253 AC: 2674 AN: 10556

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12851 AN: 68006

Other (OTH) AF: 0.180 AC: 380 AN: 2110

Alfa AF: 0.190 Hom.: 2025

Bravo AF: 0.154

Asia WGS AF: 0.382 AC: 1326 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.8
DANN	Benign	0.85
PhyloP100		-0.12
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: rs35330276; hg19: chr15-33022090;