Genetic Variant GREM1:c.-2+9G>C (chr15-32718170-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_013372.7(GREM1):c.-2+9G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,183,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

GREM1
NM_013372.7 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.703

Publications

0 publications found

Variant links:

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 links:

GREM1-AS1 (HGNC:55411): (GREM1 antisense RNA 1)

GREM1-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 15-32718170-G-C is Benign according to our data. Variant chr15-32718170-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1697739.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7 link	c.-2+9G>C	intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1	O60565-1A6XAA7
GREM1-AS1	NR_109767.1 link	n.516C>G	non_coding_transcript_exon_variant	Exon 2 of 2
GREM1	NM_001191323.2 link	c.-2+9G>C	intron_variant	Intron 1 of 2		NP_001178252.1	O60565-2
GREM1	NM_001191322.2 link	c.-2+9G>C	intron_variant	Intron 1 of 2		NP_001178251.1	B3KTR9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1 link	c.-2+9G>C		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1		O60565-1
GREM1	ENST00000560677.5 link	c.-2+9G>C		intron_variant	Intron 1 of 2	4		ENSP00000453387.1		H0YLY2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

122218

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000253

AC:

AN:

1183582

Hom.:

Cov.:

AF XY:

0.00000174

AC XY:

AN XY:

573972

show subpopulations

African (AFR)

AF:

0.0000367

AC:

AN:

27240

American (AMR)

AF:

0.00

AC:

AN:

29532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19246

East Asian (EAS)

AF:

0.00

AC:

AN:

22984

South Asian (SAS)

AF:

0.00

AC:

AN:

74358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12258

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4716

European-Non Finnish (NFE)

AF:

0.00000211

AC:

AN:

947122

Other (OTH)

AF:

0.00

AC:

AN:

46126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Likely 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

-0.69

CADD

Benign

9.6

(source)

DANN

Benign

0.86

PhyloP100

-0.70

PromoterAI

0.022

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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chr15-32718170-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over