15-32719539-TC-T

Variant names:

• chr15-32719539-TC-T
• rs72360084
• NM_013372.7:c.-2+1383delC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_013372.7(GREM1):​c.-2+1383delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 151,838 control chromosomes in the GnomAD database, including 6,601 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.27 (6601 hom., cov: 23)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00600
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 15-32719539-TC-T is Benign according to our data. Variant chr15-32719539-TC-T is described in ClinVar as [Benign]. Clinvar id is 1286829.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-2+1383delC		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.-2+842delC		intron_variant	Intron 1 of 1		NP_001355648.1
GREM1	NM_001191323.2	c.-2+1383delC		intron_variant	Intron 1 of 2		NP_001178252.1
GREM1	NM_001191322.2	c.-2+1383delC		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+1379delC		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-2+1379delC		intron_variant	Intron 1 of 2	4		ENSP00000453387.1
GREM1	ENST00000652365.1	c.-2+838delC		intron_variant	Intron 1 of 1			ENSP00000498763.1
GREM1	ENST00000560830.1	c.-2+1379delC		intron_variant	Intron 1 of 2	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41479 AN: 151720 Hom.: 6587 Cov.: 23

Gnomad AFR AF: 0.355

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.258

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

GnomAD4 genome AF: 0.274 AC: 41535 AN: 151838 Hom.: 6601 Cov.: 23 AF XY: 0.278 AC XY: 20619 AN XY: 74196

African (AFR) AF: 0.356 AC: 14724 AN: 41372

American (AMR) AF: 0.210 AC: 3208 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 653 AN: 3462

East Asian (EAS) AF: 0.684 AC: 3518 AN: 5142

South Asian (SAS) AF: 0.341 AC: 1640 AN: 4804

European-Finnish (FIN) AF: 0.300 AC: 3159 AN: 10534

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13919 AN: 67946

Other (OTH) AF: 0.264 AC: 555 AN: 2106

Alfa AF: 0.237 Hom.: 570

Bravo AF: 0.271

Asia WGS AF: 0.490 AC: 1705 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0060
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: rs72360084; hg19: chr15-33011740;