15-32718087-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_013372.7(GREM1):c.-76C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,223,544 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: 𝑓 0.00029 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: GREM1 NM_013372.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.12

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

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-32718087-C-G is Benign according to our data. Variant chr15-32718087-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1697736.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.-76C>G		5_prime_UTR_variant	1/2	ENST00000651154.1
GREM1	NM_001191322.2	c.-76C>G		5_prime_UTR_variant	1/3
GREM1	NM_001191323.2	c.-76C>G		5_prime_UTR_variant	1/3
GREM1-AS1	NR_109767.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.-76C>G		5_prime_UTR_variant	1/2		NM_013372.7	P1
GREM1-AS1	ENST00000558441.1	n.921G>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152016 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000222 AC: 6 AN: 27032 Hom.: 0 AF XY: 0.000214 AC XY: 3 AN XY: 14032

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000331

Gnomad ASJ exome AF: 0.00255

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000261

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000211 AC: 226 AN: 1071528 Hom.: 0 Cov.: 30 AF XY: 0.000196 AC XY: 100 AN XY: 510508

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000192

Gnomad4 ASJ exome AF: 0.000774

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000922

Gnomad4 FIN exome AF: 0.000568

Gnomad4 NFE exome AF: 0.000211

Gnomad4 OTH exome AF: 0.000338

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152016 Hom.: 0 Cov.: 31 AF XY: 0.000296 AC XY: 22 AN XY: 74246

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000249

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	8.0
Dann	Benign	0.91

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

LitVar

Other links and lift over

dbSNP: rs898995478; hg19: chr15-33010288;