rs17816260

Positions:

• chr15-32731484-A-C
• chr15-32731484-A-G
• chr15-32731484-A-T

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.*239A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 564,408 control chromosomes in the GnomAD database, including 92,051 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20292 hom., cov: 31)
  • Exomes 𝑓: 0.59 (71759 hom.)
• Consequence: GREM1 NM_013372.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.939

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-32731484-A-C is Benign according to our data. Variant chr15-32731484-A-C is described in ClinVar as [Benign]. Clinvar id is 1278747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.*239A>C		3_prime_UTR_variant	2/2	ENST00000651154.1
GREM1	NM_001191322.2	c.*239A>C		3_prime_UTR_variant	3/3
GREM1	NM_001191323.2	c.*239A>C		3_prime_UTR_variant	3/3
GREM1	NM_001368719.1	c.*239A>C		3_prime_UTR_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.*239A>C		3_prime_UTR_variant	2/2		NM_013372.7	P1
GREM1	ENST00000560830.1	c.*239A>C		3_prime_UTR_variant	3/3	2
GREM1	ENST00000652365.1	c.*239A>C		3_prime_UTR_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74641 AN: 151780 Hom.: 20289 Cov.: 31

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.611

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.581

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.586 AC: 241589 AN: 412510 Hom.: 71759 Cov.: 2 AF XY: 0.589 AC XY: 126261 AN XY: 214492

Gnomad4 AFR exome AF: 0.240

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.707

Gnomad4 SAS exome AF: 0.612

Gnomad4 FIN exome AF: 0.612

Gnomad4 NFE exome AF: 0.584

Gnomad4 OTH exome AF: 0.574

GnomAD4 genome AF: 0.492 AC: 74662 AN: 151898 Hom.: 20292 Cov.: 31 AF XY: 0.499 AC XY: 37019 AN XY: 74240

Gnomad4 AFR AF: 0.244

Gnomad4 AMR AF: 0.522

Gnomad4 ASJ AF: 0.606

Gnomad4 EAS AF: 0.768

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.611

Gnomad4 NFE AF: 0.581

Gnomad4 OTH AF: 0.521

Alfa AF: 0.504 Hom.: 4829

Bravo AF: 0.473

Asia WGS AF: 0.639 AC: 2225 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 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.35
DANN	Benign	0.40

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: rs17816260; hg19: chr15-33023685;