rs28768389

Variant names:

• chr15-32727362-T-C
• rs28768389
• NM_013372.7:c.-1-3328T>C

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.-1-3328T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 152,254 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.066 (421 hom., cov: 32)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.193
• Publications: 1 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=-0.96).
• BP6: Variant 15-32727362-T-C is Benign according to our data. Variant chr15-32727362-T-C is described in ClinVar as Benign. ClinVar VariationId is 1179364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0975 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013372.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	NM_013372.7	MANE Select	c.-1-3328T>C		intron	N/A	NP_037504.1
	GREM1	NM_001368719.1		c.-1-3328T>C		intron	N/A	NP_001355648.1
	GREM1	NM_001191323.2		c.-1-3328T>C		intron	N/A	NP_001178252.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	ENST00000651154.1	MANE Select	c.-1-3328T>C		intron	N/A	ENSP00000498748.1
	GREM1	ENST00000560677.5	TSL:4	c.-1-3328T>C		intron	N/A	ENSP00000453387.1
	GREM1	ENST00000652365.1		c.-1-3328T>C		intron	N/A	ENSP00000498763.1

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10087 AN: 152136 Hom.: 421 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0635

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0886

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.0799

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

GnomAD4 genome AF: 0.0663 AC: 10092 AN: 152254 Hom.: 421 Cov.: 32 AF XY: 0.0643 AC XY: 4783 AN XY: 74436

African (AFR) AF: 0.0190 AC: 789 AN: 41552

American (AMR) AF: 0.0688 AC: 1053 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0635 AC: 220 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4826

European-Finnish (FIN) AF: 0.0886 AC: 939 AN: 10602

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6768 AN: 68008

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0303 Hom.: 26

Bravo AF: 0.0637

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.8
DANN	Benign	0.46
PhyloP100		0.19
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: rs28768389; hg19: chr15-33019563; COSMIC: COSV55714368;