rs3207357

Variant names:

• chr15-32718282-T-C
• rs3207357
• NM_013372.7:c.-2+121T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0880
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 1247744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0966 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013372.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	NM_013372.7	MANE Select	c.-2+121T>C		intron	N/A	NP_037504.1
	GREM1-AS1	NR_109767.1		n.404A>G		non_coding_transcript_exon	Exon 2 of 2
	GREM1	NM_001191323.2		c.-2+121T>C		intron	N/A	NP_001178252.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	ENST00000651154.1	MANE Select	c.-2+121T>C		intron	N/A	ENSP00000498748.1
	GREM1	ENST00000560677.5	TSL:4	c.-2+121T>C		intron	N/A	ENSP00000453387.1
	GREM1-AS1	ENST00000558441.1	TSL:6	n.726A>G		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.0621 AC: 8316 AN: 133822 AF XY: 0.0612

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 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

African (AFR) AF: 0.0182 AC: 284 AN: 15562

American (AMR) AF: 0.0523 AC: 1530 AN: 29274

Ashkenazi Jewish (ASJ) AF: 0.0485 AC: 772 AN: 15904

East Asian (EAS) AF: 0.000258 AC: 5 AN: 19416

South Asian (SAS) AF: 0.0205 AC: 1328 AN: 64814

European-Finnish (FIN) AF: 0.0836 AC: 1071 AN: 12812

Middle Eastern (MID) AF: 0.0869 AC: 314 AN: 3612

European-Non Finnish (NFE) AF: 0.102 AC: 40689 AN: 399992

Other (OTH) AF: 0.0799 AC: 2108 AN: 26390

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

African (AFR) AF: 0.0177 AC: 736 AN: 41538

American (AMR) AF: 0.0680 AC: 1041 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 166 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.0191 AC: 92 AN: 4818

European-Finnish (FIN) AF: 0.0875 AC: 928 AN: 10606

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0986 AC: 6704 AN: 67978

Other (OTH) AF: 0.0762 AC: 161 AN: 2112

Alfa AF: 0.0824 Hom.: 177

Bravo AF: 0.0627

Asia WGS AF: 0.0120 AC: 40 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.2
DANN	Benign	0.23
PhyloP100		0.088
PromoterAI		0.0084	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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