15-32731469-C-T

Variant names:

• chr15-32731469-C-T
• rs33963919
• NM_013372.7:c.*224C>T

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.*224C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 584,906 control chromosomes in the GnomAD database, including 94,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20282 hom., cov: 31)
  • Exomes 𝑓: 0.58 (74629 hom.)
• Consequence: GREM1 NM_013372.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.215
• Publications: 9 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=-0.77).
• BP6: Variant 15-32731469-C-T is Benign according to our data. Variant chr15-32731469-C-T is described in ClinVar as Benign. ClinVar VariationId is 1222045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM1	NM_013372.7	c.*224C>T		3_prime_UTR_variant	Exon 2 of 2	ENST00000651154.1	NP_037504.1
GREM1	NM_001368719.1	c.*224C>T		3_prime_UTR_variant	Exon 2 of 2		NP_001355648.1
GREM1	NM_001191323.2	c.*224C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001178252.1
GREM1	NM_001191322.2	c.*224C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001178251.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM1	ENST00000651154.1	c.*224C>T		3_prime_UTR_variant	Exon 2 of 2		NM_013372.7	ENSP00000498748.1
GREM1	ENST00000652365.1	c.*224C>T		3_prime_UTR_variant	Exon 2 of 2			ENSP00000498763.1
GREM1	ENST00000560830.1	c.*224C>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000453141.1
GREM1	ENST00000560677.5	c.*529C>T		downstream_gene_variant		4		ENSP00000453387.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74616 AN: 151798 Hom.: 20278 Cov.: 31

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.582 AC: 252042 AN: 432992 Hom.: 74629 Cov.: 2 AF XY: 0.585 AC XY: 132065 AN XY: 225844

African (AFR) AF: 0.236 AC: 2802 AN: 11862

American (AMR) AF: 0.517 AC: 8033 AN: 15552

Ashkenazi Jewish (ASJ) AF: 0.591 AC: 7808 AN: 13212

East Asian (EAS) AF: 0.704 AC: 20856 AN: 29604

South Asian (SAS) AF: 0.603 AC: 23095 AN: 38298

European-Finnish (FIN) AF: 0.610 AC: 26071 AN: 42712

Middle Eastern (MID) AF: 0.578 AC: 1091 AN: 1886

European-Non Finnish (NFE) AF: 0.581 AC: 148130 AN: 255074

Other (OTH) AF: 0.571 AC: 14156 AN: 24792

GnomAD4 genome AF: 0.491 AC: 74638 AN: 151914 Hom.: 20282 Cov.: 31 AF XY: 0.498 AC XY: 37004 AN XY: 74238

African (AFR) AF: 0.243 AC: 10076 AN: 41410

American (AMR) AF: 0.522 AC: 7968 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 2104 AN: 3472

East Asian (EAS) AF: 0.768 AC: 3938 AN: 5128

South Asian (SAS) AF: 0.620 AC: 2979 AN: 4804

European-Finnish (FIN) AF: 0.610 AC: 6445 AN: 10558

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39443 AN: 67954

Other (OTH) AF: 0.521 AC: 1099 AN: 2110

Alfa AF: 0.502 Hom.: 8339

Bravo AF: 0.472

Asia WGS AF: 0.638 AC: 2221 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.9
DANN	Benign	0.53
PhyloP100		0.21
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: rs33963919; hg19: chr15-33023670;