rs28768389

chr15-32727362-T-C

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.-1-3328T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 152,254 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.066 (421 hom., cov: 32)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.193

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 15-32727362-T-C is Benign according to our data. Variant chr15-32727362-T-C is described in ClinVar as [Benign]. Clinvar id is 1179364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0975 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.-1-3328T>C		intron_variant		ENST00000651154.1
GREM1	NM_001191322.2	c.-1-3328T>C		intron_variant
GREM1	NM_001191323.2	c.-1-3328T>C		intron_variant
GREM1	NM_001368719.1	c.-1-3328T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.-1-3328T>C		intron_variant			NM_013372.7	P1
GREM1	ENST00000560677.5	c.-1-3328T>C		intron_variant		4
GREM1	ENST00000560830.1	c.-1-3328T>C		intron_variant		2
GREM1	ENST00000652365.1	c.-1-3328T>C		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10087 AN: 152136 Hom.: 421 Cov.: 32

Gnomad AFR AF: 0.0189

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0635

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.0886

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.0799

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0663 AC: 10092 AN: 152254 Hom.: 421 Cov.: 32 AF XY: 0.0643 AC XY: 4783 AN XY: 74436

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.0688

Gnomad4 ASJ AF: 0.0635

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.0886

Gnomad4 NFE AF: 0.0995

Gnomad4 OTH AF: 0.0791

Alfa AF: 0.0303 Hom.: 26

Bravo AF: 0.0637

Asia WGS AF: 0.0130 AC: 46 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 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	3.8
Dann	Benign	0.46

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: rs28768389; hg19: chr15-33019563; COSMIC: COSV55714368;