15-32718535-G-A

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+374G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 454,108 control chromosomes in the GnomAD database, including 16,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (5307 hom., cov: 32)
  • Exomes 𝑓: 0.25 (10811 hom.)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.129

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=-0.71).
• BP6: Variant 15-32718535-G-A is Benign according to our data. Variant chr15-32718535-G-A is described in ClinVar as [Benign]. Clinvar id is 1240993.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.-2+374G>A		intron_variant		ENST00000651154.1
GREM1-AS1	NR_109767.1	n.321+10C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+374G>A		intron_variant			NM_013372.7	P1
GREM1-AS1	ENST00000558441.1	n.473C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37229 AN: 151936 Hom.: 5295 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.266 AC: 33897 AN: 127344 Hom.: 5768 AF XY: 0.271 AC XY: 18911 AN XY: 69888

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.697

Gnomad SAS exome AF: 0.318

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.247 AC: 74556 AN: 302054 Hom.: 10811 Cov.: 0 AF XY: 0.255 AC XY: 43781 AN XY: 171870

Gnomad4 AFR exome AF: 0.253

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.688

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.290

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.249

GnomAD4 genome AF: 0.245 AC: 37278 AN: 152054 Hom.: 5307 Cov.: 32 AF XY: 0.250 AC XY: 18598 AN XY: 74326

Gnomad4 AFR AF: 0.264

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.688

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.241

Alfa AF: 0.207 Hom.: 1148

Bravo AF: 0.239

Asia WGS AF: 0.484 AC: 1680 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 06, 2018

This variant is associated with the following publications: (PMID: 27379672) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	10
Dann	Benign	0.92

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: rs2293581; hg19: chr15-33010736; COSMIC: COSV104411391;