NM_013372.7:c.-1-1963T>G

Variant names:

• chr15-32728727-T-G
• rs16973303
• NM_013372.7:c.-1-1963T>G

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.-1-1963T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 151,972 control chromosomes in the GnomAD database, including 28,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.60 (28500 hom., cov: 31)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.921
• Publications: 3 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, G2P, Orphanet
• 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=-0.9).
• BP6: Variant 15-32728727-T-G is Benign according to our data. Variant chr15-32728727-T-G is described in ClinVar as Benign. ClinVar VariationId is 1223202.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.746 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	NM_013372.7	MANE Select	c.-1-1963T>G		intron	N/A	NP_037504.1	A6XAA7
	GREM1	NM_001368719.1		c.-1-1963T>G		intron	N/A	NP_001355648.1	O60565-1
	GREM1	NM_001191323.2		c.-1-1963T>G		intron	N/A	NP_001178252.1	O60565-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	ENST00000651154.1	MANE Select	c.-1-1963T>G		intron	N/A	ENSP00000498748.1	O60565-1
	GREM1	ENST00000560677.5	TSL:4	c.-1-1963T>G		intron	N/A	ENSP00000453387.1	H0YLY2
	GREM1	ENST00000652365.1		c.-1-1963T>G		intron	N/A	ENSP00000498763.1	O60565-1

Frequencies

GnomAD3 genomes AF: 0.596 AC: 90577 AN: 151854 Hom.: 28493 Cov.: 31

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.670

Gnomad EAS AF: 0.767

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.699

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.688

Gnomad OTH AF: 0.624

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

GnomAD4 genome AF: 0.596 AC: 90620 AN: 151972 Hom.: 28500 Cov.: 31 AF XY: 0.600 AC XY: 44566 AN XY: 74288

African (AFR) AF: 0.380 AC: 15767 AN: 41456

American (AMR) AF: 0.611 AC: 9325 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 2326 AN: 3472

East Asian (EAS) AF: 0.766 AC: 3945 AN: 5150

South Asian (SAS) AF: 0.650 AC: 3134 AN: 4820

European-Finnish (FIN) AF: 0.699 AC: 7374 AN: 10548

Middle Eastern (MID) AF: 0.668 AC: 195 AN: 292

European-Non Finnish (NFE) AF: 0.688 AC: 46763 AN: 67958

Other (OTH) AF: 0.628 AC: 1328 AN: 2114

Alfa AF: 0.667 Hom.: 15068

Bravo AF: 0.579

Asia WGS AF: 0.661 AC: 2300 AN: 3478

ClinVar

ClinVar submissions

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	-0.90
CADD	Benign	0.46
DANN	Benign	0.38
PhyloP100		-0.92
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: rs16973303; hg19: chr15-33020928;