15-32719496-G-C

Variant names:

• chr15-32719496-G-C
• rs79207432
• NM_013372.7:c.-2+1335G>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.-2+1335G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 152,034 control chromosomes in the GnomAD database, including 3,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (3658 hom., cov: 32)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.435
• Publications: 8 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=-0.81).
• BP6: Variant 15-32719496-G-C is Benign according to our data. Variant chr15-32719496-G-C is described in ClinVar as [Benign]. Clinvar id is 1238271.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-2+1335G>C		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.-2+794G>C		intron_variant	Intron 1 of 1		NP_001355648.1
GREM1	NM_001191323.2	c.-2+1335G>C		intron_variant	Intron 1 of 2		NP_001178252.1
GREM1	NM_001191322.2	c.-2+1335G>C		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+1335G>C		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-2+1335G>C		intron_variant	Intron 1 of 2	4		ENSP00000453387.1
GREM1	ENST00000652365.1	c.-2+794G>C		intron_variant	Intron 1 of 1			ENSP00000498763.1
GREM1	ENST00000560830.1	c.-2+1335G>C		intron_variant	Intron 1 of 2	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31990 AN: 151916 Hom.: 3658 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.210

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

GnomAD4 genome AF: 0.210 AC: 32003 AN: 152034 Hom.: 3658 Cov.: 32 AF XY: 0.214 AC XY: 15898 AN XY: 74292

African (AFR) AF: 0.183 AC: 7592 AN: 41484

American (AMR) AF: 0.189 AC: 2890 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 579 AN: 3470

East Asian (EAS) AF: 0.485 AC: 2493 AN: 5138

South Asian (SAS) AF: 0.310 AC: 1492 AN: 4818

European-Finnish (FIN) AF: 0.261 AC: 2745 AN: 10534

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13608 AN: 67980

Other (OTH) AF: 0.214 AC: 451 AN: 2112

Alfa AF: 0.109 Hom.: 185

Bravo AF: 0.204

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 06, 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	-0.81
CADD	Benign	2.3
DANN	Benign	0.62
PhyloP100		-0.43
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: rs79207432; hg19: chr15-33011697;