15-32718535-G-A

Variant names:

• chr15-32718535-G-A
• rs2293581
• NM_013372.7:c.-2+374G>A

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+374G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 454,108 control chromosomes in the GnomAD database, including 16,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5307 hom., cov: 32)
  • Exomes 𝑓: 0.25 (10811 hom.)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.129
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 15-32718535-G-A is Benign according to our data. Variant chr15-32718535-G-A is described in ClinVar as [Benign]. Clinvar id is 1240993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-2+374G>A		intron_variant	Intron 1 of 1	ENST00000651154.1	NP_037504.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+374G>A		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-2+374G>A		intron_variant	Intron 1 of 2	4		ENSP00000453387.1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37229 AN: 151936 Hom.: 5295 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.0879

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.236

GnomAD2 exomes AF: 0.266 AC: 33897 AN: 127344 AF XY: 0.271

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.167

Gnomad EAS exome AF: 0.697

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.247 AC: 74556 AN: 302054 Hom.: 10811 Cov.: 0 AF XY: 0.255 AC XY: 43781 AN XY: 171870

African (AFR) AF: 0.253 AC: 2108 AN: 8336

American (AMR) AF: 0.198 AC: 5270 AN: 26556

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 1806 AN: 10736

East Asian (EAS) AF: 0.688 AC: 6582 AN: 9562

South Asian (SAS) AF: 0.316 AC: 18815 AN: 59546

European-Finnish (FIN) AF: 0.290 AC: 3557 AN: 12262

Middle Eastern (MID) AF: 0.187 AC: 516 AN: 2760

European-Non Finnish (NFE) AF: 0.205 AC: 32372 AN: 158132

Other (OTH) AF: 0.249 AC: 3530 AN: 14164

GnomAD4 genome AF: 0.245 AC: 37278 AN: 152054 Hom.: 5307 Cov.: 32 AF XY: 0.250 AC XY: 18598 AN XY: 74326

African (AFR) AF: 0.264 AC: 10944 AN: 41494

American (AMR) AF: 0.198 AC: 3029 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 569 AN: 3464

East Asian (EAS) AF: 0.688 AC: 3521 AN: 5116

South Asian (SAS) AF: 0.337 AC: 1626 AN: 4826

European-Finnish (FIN) AF: 0.299 AC: 3162 AN: 10586

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

European-Non Finnish (NFE) AF: 0.203 AC: 13775 AN: 67954

Other (OTH) AF: 0.241 AC: 510 AN: 2114

Alfa AF: 0.218 Hom.: 5519

Bravo AF: 0.239

Asia WGS AF: 0.484 AC: 1680 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27379672) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.92
PhyloP100		0.13
PromoterAI		0.22	Neutral
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: rs2293581; hg19: chr15-33010736; COSMIC: COSV104411391;