15-32718282-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013372.7(GREM1):c.-2+121T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0784 in 739,950 control chromosomes in the GnomAD database, including 2,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.065 (415 hom., cov: 32)
  • Exomes 𝑓: 0.082 (2314 hom.)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0880

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 15-32718282-T-C is Benign according to our data. Variant chr15-32718282-T-C is described in ClinVar as [Benign]. Clinvar id is 1247744.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.-2+121T>C		intron_variant		ENST00000651154.1
GREM1-AS1	NR_109767.1	n.404A>G		non_coding_transcript_exon_variant	2/2
GREM1	NM_001191322.2	c.-2+121T>C		intron_variant
GREM1	NM_001191323.2	c.-2+121T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+121T>C		intron_variant			NM_013372.7	P1
GREM1-AS1	ENST00000558441.1	n.726A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 9898 AN: 152062 Hom.: 415 Cov.: 32

Gnomad AFR AF: 0.0177

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.0681

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0187

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0986

Gnomad OTH AF: 0.0770

GnomAD3 exomes AF: 0.0621 AC: 8316 AN: 133822 Hom.: 356 AF XY: 0.0612 AC XY: 4467 AN XY: 72998

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0517

Gnomad ASJ exome AF: 0.0486

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0230

Gnomad FIN exome AF: 0.0841

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.0795

GnomAD4 exome AF: 0.0818 AC: 48101 AN: 587776 Hom.: 2314 Cov.: 8 AF XY: 0.0787 AC XY: 24192 AN XY: 307348

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.0523

Gnomad4 ASJ exome AF: 0.0485

Gnomad4 EAS exome AF: 0.000258

Gnomad4 SAS exome AF: 0.0205

Gnomad4 FIN exome AF: 0.0836

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.0799

GnomAD4 genome AF: 0.0651 AC: 9900 AN: 152174 Hom.: 415 Cov.: 32 AF XY: 0.0631 AC XY: 4698 AN XY: 74406

Gnomad4 AFR AF: 0.0177

Gnomad4 AMR AF: 0.0680

Gnomad4 ASJ AF: 0.0478

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.0875

Gnomad4 NFE AF: 0.0986

Gnomad4 OTH AF: 0.0762

Alfa AF: 0.0835 Hom.: 177

Bravo AF: 0.0627

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	7.2
Dann	Benign	0.23

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: rs3207357; hg19: chr15-33010483; COSMIC: COSV55714430;