15-32718926-G-A

Variant names:

• chr15-32718926-G-A
• rs7168877
• NM_013372.7:c.-2+765G>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+765G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 184,916 control chromosomes in the GnomAD database, including 7,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6388 hom., cov: 34)
  • Exomes 𝑓: 0.29 (1440 hom.)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.46
• Publications: 2 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=-0.73).
• BP6: Variant 15-32718926-G-A is Benign according to our data. Variant chr15-32718926-G-A is described in ClinVar as [Benign]. Clinvar id is 1253065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.347 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.-2+765G>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+765G>A		intron_variant	Intron 1 of 1		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000560677.5	c.-2+765G>A		intron_variant	Intron 1 of 2	4		ENSP00000453387.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43754 AN: 152042 Hom.: 6385 Cov.: 34

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.268

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.281

GnomAD4 exome AF: 0.286 AC: 9362 AN: 32754 Hom.: 1440 Cov.: 0 AF XY: 0.288 AC XY: 4916 AN XY: 17046

African (AFR) AF: 0.264 AC: 68 AN: 258

American (AMR) AF: 0.359 AC: 1043 AN: 2904

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 162 AN: 520

East Asian (EAS) AF: 0.269 AC: 510 AN: 1896

South Asian (SAS) AF: 0.359 AC: 1340 AN: 3732

European-Finnish (FIN) AF: 0.264 AC: 358 AN: 1358

Middle Eastern (MID) AF: 0.306 AC: 30 AN: 98

European-Non Finnish (NFE) AF: 0.267 AC: 5423 AN: 20332

Other (OTH) AF: 0.258 AC: 428 AN: 1656

GnomAD4 genome AF: 0.288 AC: 43770 AN: 152162 Hom.: 6388 Cov.: 34 AF XY: 0.289 AC XY: 21521 AN XY: 74390

African (AFR) AF: 0.283 AC: 11772 AN: 41528

American (AMR) AF: 0.355 AC: 5429 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1075 AN: 3470

East Asian (EAS) AF: 0.270 AC: 1389 AN: 5148

South Asian (SAS) AF: 0.357 AC: 1725 AN: 4830

European-Finnish (FIN) AF: 0.268 AC: 2845 AN: 10598

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18517 AN: 67974

Other (OTH) AF: 0.278 AC: 586 AN: 2110

Alfa AF: 0.254 Hom.: 2223

Bravo AF: 0.292

Asia WGS AF: 0.309 AC: 1072 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 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	-0.73
CADD	Benign	10
DANN	Benign	0.84
PhyloP100		1.5
PromoterAI		-0.023	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: rs7168877; hg19: chr15-33011127;