chr15-32720301-A-G

Variant names:

• chr15-32720301-A-G
• rs73376930
• NM_013372.7:c.-2+2140A>G

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+2140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 152,070 control chromosomes in the GnomAD database, including 5,281 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.25 (5281 hom., cov: 32)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0870
• Publications: 30 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 Gene-Disease associations (from GenCC):

• hereditary mixed polyposis syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P
• polyposis syndrome, hereditary mixed, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-32720301-A-G is Benign according to our data. Variant chr15-32720301-A-G is described in ClinVar as [Benign]. Clinvar id is 1241475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.472 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-2+2140A>G		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.-2+1599A>G		intron_variant	Intron 1 of 1		NP_001355648.1
GREM1	NM_001191323.2	c.-2+2140A>G		intron_variant	Intron 1 of 2		NP_001178252.1
GREM1	NM_001191322.2	c.-2+2140A>G		intron_variant	Intron 1 of 2		NP_001178251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+2140A>G		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-2+2140A>G		intron_variant	Intron 1 of 2	4		ENSP00000453387.1
GREM1	ENST00000652365.1	c.-2+1599A>G		intron_variant	Intron 1 of 1			ENSP00000498763.1
GREM1	ENST00000560830.1	c.-2+2140A>G		intron_variant	Intron 1 of 2	2		ENSP00000453141.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38106 AN: 151952 Hom.: 5271 Cov.: 32

Gnomad AFR AF: 0.335

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.251 AC: 38149 AN: 152070 Hom.: 5281 Cov.: 32 AF XY: 0.254 AC XY: 18853 AN XY: 74334

African (AFR) AF: 0.335 AC: 13880 AN: 41458

American (AMR) AF: 0.194 AC: 2963 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 494 AN: 3472

East Asian (EAS) AF: 0.488 AC: 2522 AN: 5168

South Asian (SAS) AF: 0.313 AC: 1504 AN: 4806

European-Finnish (FIN) AF: 0.261 AC: 2757 AN: 10576

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13389 AN: 67994

Other (OTH) AF: 0.235 AC: 498 AN: 2116

Alfa AF: 0.215 Hom.: 6868

Bravo AF: 0.250

Asia WGS AF: 0.410 AC: 1424 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial colorectal cancer Benign:1

Sep 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jul 05, 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	-0.86
CADD	Benign	2.8
DANN	Benign	0.42
PhyloP100		-0.087
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: rs73376930; hg19: chr15-33012502;