15-32717891-G-T

Variant names:

• chr15-32717891-G-T
• rs12324639
• ENST00000908783.1:c.-2+781G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000908783.1(GREM1):​c.-2+781G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 438,894 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (142 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (29 hom.)
• Consequence: GREM1 ENST00000908783.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.14
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 15-32717891-G-T is Benign according to our data. Variant chr15-32717891-G-T is described in ClinVar as Benign. ClinVar VariationId is 1253919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0818 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000908783.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	NM_013372.7	MANE Select	c.-272G>T		upstream_gene	N/A	NP_037504.1	A6XAA7
	GREM1	NM_001191323.2		c.-272G>T		upstream_gene	N/A	NP_001178252.1	O60565-2
	GREM1	NM_001191322.2		c.-272G>T		upstream_gene	N/A	NP_001178251.1	B3KTR9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	ENST00000908783.1		c.-2+781G>T		intron	N/A	ENSP00000578842.1
	GREM1-AS1	ENST00000558441.1	TSL:6	n.1117C>A		non_coding_transcript_exon	Exon 1 of 1
	GREM1	ENST00000651154.1	MANE Select	c.-272G>T		upstream_gene	N/A	ENSP00000498748.1	O60565-1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3656 AN: 151720 Hom.: 139 Cov.: 31

Gnomad AFR AF: 0.0839

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0192

GnomAD4 exome AF: 0.00251 AC: 720 AN: 287064 Hom.: 29 Cov.: 5 AF XY: 0.00222 AC XY: 301 AN XY: 135818

African (AFR) AF: 0.0883 AC: 568 AN: 6434

American (AMR) AF: 0.00952 AC: 15 AN: 1576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4332

East Asian (EAS) AF: 0.00 AC: 0 AN: 8328

South Asian (SAS) AF: 0.000186 AC: 1 AN: 5374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 164

Middle Eastern (MID) AF: 0.00260 AC: 2 AN: 768

European-Non Finnish (NFE) AF: 0.000209 AC: 52 AN: 248418

Other (OTH) AF: 0.00703 AC: 82 AN: 11670

GnomAD4 genome AF: 0.0242 AC: 3678 AN: 151830 Hom.: 142 Cov.: 31 AF XY: 0.0228 AC XY: 1691 AN XY: 74218

African (AFR) AF: 0.0842 AC: 3484 AN: 41390

American (AMR) AF: 0.00817 AC: 125 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67898

Other (OTH) AF: 0.0190 AC: 40 AN: 2108

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.0272

Asia WGS AF: 0.00435 AC: 15 AN: 3464

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	-0.36
CADD	Benign	19
DANN	Benign	0.96
PhyloP100		2.1
PromoterAI		0.096	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12324639; hg19: chr15-33010092;