rs1057519288

Positions:

• chr1-240493068-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_022469.4(GREM2):​c.408G>T​(p.Glu136Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GREM2 NM_022469.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -1.45

Genes affected

GREM2 (HGNC:17655): (gremlin 2, 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-240493068-C-A is Pathogenic according to our data. Variant chr1-240493068-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 374885.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18081954). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GREM2	NM_022469.4	c.408G>T	p.Glu136Asp	missense_variant	2/2	ENST00000318160.5	NP_071914.3
GREM2	XM_047427832.1	c.462G>T	p.Glu154Asp	missense_variant	3/3		XP_047283788.1
GREM2	XM_047427839.1	c.462G>T	p.Glu154Asp	missense_variant	4/4		XP_047283795.1
GREM2	XM_011544249.3	c.408G>T	p.Glu136Asp	missense_variant	3/3		XP_011542551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GREM2	ENST00000318160.5	c.408G>T	p.Glu136Asp	missense_variant	2/2	1	NM_022469.4	ENSP00000318650.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Tooth agenesis, selective, 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.0070
DANN	Benign	0.90
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.3	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.49	N
REVEL	Benign	0.085
Sift	Benign	0.62	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.62
MutPred		0.53		Gain of sheet (P = 0.1451);
MVP		0.15
MPC		0.73
ClinPred		0.18	T
GERP RS		-9.9
Varity_R		0.062
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs1057519288; hg19: chr1-240656368;