NM_013372.7:c.-49G>A

Variant names:

• chr15-32718114-G-A
• rs535570187
• NM_013372.7:c.-49G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_013372.7(GREM1):​c.-49G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,272,878 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: GREM1 NM_013372.7 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.101
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 15-32718114-G-A is Benign according to our data. Variant chr15-32718114-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1697737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 35 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	NM_013372.7	MANE Select	c.-49G>A		5_prime_UTR	Exon 1 of 2	NP_037504.1	A6XAA7
	GREM1	NM_001191323.2		c.-49G>A		5_prime_UTR	Exon 1 of 3	NP_001178252.1	O60565-2
	GREM1	NM_001191322.2		c.-49G>A		5_prime_UTR	Exon 1 of 3	NP_001178251.1	B3KTR9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GREM1	ENST00000651154.1	MANE Select	c.-49G>A		5_prime_UTR	Exon 1 of 2	ENSP00000498748.1	O60565-1
	GREM1	ENST00000560677.5	TSL:4	c.-49G>A		5_prime_UTR	Exon 1 of 3	ENSP00000453387.1	H0YLY2
	GREM1	ENST00000560830.1	TSL:2	c.-49G>A		5_prime_UTR	Exon 1 of 3	ENSP00000453141.1	O60565-2

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 151988 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000171 AC: 11 AN: 64352 AF XY: 0.000178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000470

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000215 AC: 241 AN: 1120776 Hom.: 0 Cov.: 30 AF XY: 0.000192 AC XY: 103 AN XY: 537108

African (AFR) AF: 0.00 AC: 0 AN: 24606

American (AMR) AF: 0.00 AC: 0 AN: 18418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14792

East Asian (EAS) AF: 0.00 AC: 0 AN: 22224

South Asian (SAS) AF: 0.00 AC: 0 AN: 63424

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3928

European-Non Finnish (NFE) AF: 0.000254 AC: 234 AN: 920550

Other (OTH) AF: 0.000161 AC: 7 AN: 43524

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152102 Hom.: 1 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74350

African (AFR) AF: 0.0000481 AC: 2 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000471 AC: 32 AN: 67946

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000170

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		0.10
PromoterAI		0.022	Neutral
Mutation Taster		=280/20	polymorphism

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: rs535570187; hg19: chr15-33010315;