15-32719650-G-T

Variant names:

• chr15-32719650-G-T
• rs8034965
• NM_013372.7:c.-2+1489G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6_Moderate BA1

The NM_013372.7(GREM1):​c.-2+1489G>T variant causes a intron change. The variant allele was found at a frequency of 0.268 in 151,968 control chromosomes in the GnomAD database, including 6,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.27 (6337 hom., cov: 32)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.12
• Publications: 9 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16).
• BP6: Variant 15-32719650-G-T is Benign according to our data. Variant chr15-32719650-G-T is described in ClinVar as [Benign]. Clinvar id is 1281851.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-2+1489G>T		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.-2+948G>T		intron_variant	Intron 1 of 1		NP_001355648.1
GREM1	NM_001191323.2	c.-2+1489G>T		intron_variant	Intron 1 of 2		NP_001178252.1
GREM1	NM_001191322.2	c.-2+1489G>T		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.-2+1489G>T		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-2+1489G>T		intron_variant	Intron 1 of 2	4		ENSP00000453387.1
GREM1	ENST00000652365.1	c.-2+948G>T		intron_variant	Intron 1 of 1			ENSP00000498763.1
GREM1	ENST00000560830.1	c.-2+1489G>T		intron_variant	Intron 1 of 2	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40630 AN: 151850 Hom.: 6321 Cov.: 32

Gnomad AFR AF: 0.342

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.688

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.252

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

GnomAD4 genome AF: 0.268 AC: 40688 AN: 151968 Hom.: 6337 Cov.: 32 AF XY: 0.272 AC XY: 20233 AN XY: 74282

African (AFR) AF: 0.342 AC: 14172 AN: 41432

American (AMR) AF: 0.204 AC: 3115 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 571 AN: 3466

East Asian (EAS) AF: 0.686 AC: 3529 AN: 5144

South Asian (SAS) AF: 0.339 AC: 1627 AN: 4806

European-Finnish (FIN) AF: 0.298 AC: 3152 AN: 10562

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.204 AC: 13836 AN: 67966

Other (OTH) AF: 0.257 AC: 542 AN: 2106

Alfa AF: 0.219 Hom.: 2068

Bravo AF: 0.265

Asia WGS AF: 0.489 AC: 1699 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 05, 2018

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	-0.16
CADD	Benign	19
DANN	Benign	0.85
PhyloP100		4.1
Mutation Taster		=98/2	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: rs8034965; hg19: chr15-33011851;