chr15-32730381-A-T

Variant names:

• chr15-32730381-A-T
• rs11854391
• NM_013372.7:c.-1-309A>T

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.-1-309A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.58 in 152,042 control chromosomes in the GnomAD database, including 27,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.58 (27497 hom., cov: 31)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.407
• 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, 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=-0.91).
• BP6: Variant 15-32730381-A-T is Benign according to our data. Variant chr15-32730381-A-T is described in ClinVar as Benign. ClinVar VariationId is 1234007.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.745 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.-1-309A>T		intron	N/A	NP_037504.1	A6XAA7
	GREM1	NM_001368719.1		c.-1-309A>T		intron	N/A	NP_001355648.1	O60565-1
	GREM1	NM_001191323.2		c.-1-309A>T		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.-1-309A>T		intron	N/A	ENSP00000498748.1	O60565-1
	GREM1	ENST00000560677.5	TSL:4	c.-1-309A>T		intron	N/A	ENSP00000453387.1	H0YLY2
	GREM1	ENST00000652365.1		c.-1-309A>T		intron	N/A	ENSP00000498763.1	O60565-1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 88073 AN: 151924 Hom.: 27488 Cov.: 31

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.599

Gnomad ASJ AF: 0.669

Gnomad EAS AF: 0.766

Gnomad SAS AF: 0.639

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.650

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.613

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

GnomAD4 genome AF: 0.580 AC: 88109 AN: 152042 Hom.: 27497 Cov.: 31 AF XY: 0.583 AC XY: 43356 AN XY: 74304

African (AFR) AF: 0.331 AC: 13728 AN: 41462

American (AMR) AF: 0.599 AC: 9141 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.669 AC: 2320 AN: 3468

East Asian (EAS) AF: 0.765 AC: 3947 AN: 5158

South Asian (SAS) AF: 0.642 AC: 3095 AN: 4824

European-Finnish (FIN) AF: 0.700 AC: 7396 AN: 10570

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.685 AC: 46536 AN: 67980

Other (OTH) AF: 0.617 AC: 1299 AN: 2106

Alfa AF: 0.630 Hom.: 3913

Bravo AF: 0.561

Asia WGS AF: 0.653 AC: 2275 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	-0.91
CADD	Benign	1.4
DANN	Benign	0.47
PhyloP100		-0.41
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: rs11854391; hg19: chr15-33022582;