15-32718926-G-A

Position:

• chr15-32718926-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_013372.7(GREM1):​c.-2+765G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 184,916 control chromosomes in the GnomAD database, including 7,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6388 hom., cov: 34)
  • Exomes 𝑓: 0.29 (1440 hom.)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-32718926-G-A is Benign according to our data. Variant chr15-32718926-G-A is described in ClinVar as [Benign]. Clinvar id is 1253065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.-2+765G>A		intron_variant		ENST00000651154.1
GREM1	NM_001191322.2	c.-2+765G>A		intron_variant
GREM1	NM_001191323.2	c.-2+765G>A		intron_variant
GREM1	NM_001368719.1	c.-2+224G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+765G>A		intron_variant			NM_013372.7	P1
GREM1-AS1	ENST00000558441.1	n.82C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43754 AN: 152042 Hom.: 6385 Cov.: 34

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.286 AC: 9362 AN: 32754 Hom.: 1440 Cov.: 0 AF XY: 0.288 AC XY: 4916 AN XY: 17046

Gnomad4 AFR exome AF: 0.264

Gnomad4 AMR exome AF: 0.359

Gnomad4 ASJ exome AF: 0.312

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.264

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.288 AC: 43770 AN: 152162 Hom.: 6388 Cov.: 34 AF XY: 0.289 AC XY: 21521 AN XY: 74390

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.355

Gnomad4 ASJ AF: 0.310

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.357

Gnomad4 FIN AF: 0.268

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.278

Alfa AF: 0.226 Hom.: 954

Bravo AF: 0.292

Asia WGS AF: 0.309 AC: 1072 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.84

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: rs7168877; hg19: chr15-33011127;