Genetic Variant GREM1:c.-2+121T>C (chr15-32718282-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0880

Publications

3 publications found

Variant links:

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 links:

GREM1-AS1 (HGNC:55411): (GREM1 antisense RNA 1)

GREM1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7 link	c.-2+121T>C		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1	O60565-1A6XAA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1 link	c.-2+121T>C		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1		O60565-1
GREM1	ENST00000560677.5 link	c.-2+121T>C		intron_variant	Intron 1 of 2	4		ENSP00000453387.1		H0YLY2

Frequencies

GnomAD3 genomes

AF:

0.0651

AC:

9898

AN:

152062

Hom.:

415

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0787

AC XY:

24192

AN XY:

307348

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

2566

5133

7699

10266

12832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0651

AC:

9900

AN:

152174

Hom.:

415

Cov.:

AF XY:

0.0631

AC XY:

4698

AN XY:

74406

show subpopulations

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:

AN:

5150

South Asian (SAS)

AF:

0.0191

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0875

AC:

928

AN:

10606

Middle Eastern (MID)

AF:

0.0582

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0986

AC:

6704

AN:

67978

Other (OTH)

AF:

0.0762

AC:

161

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

471

943

1414

1886

2357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0824

Hom.:

177

Bravo

AF:

0.0627

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.2

(source)

DANN

Benign

0.23

PhyloP100

0.088

PromoterAI

0.0084

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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15-32718282-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over