chr1-240493469-A-C

Variant names:

• chr1-240493469-A-C
• rs201326333
• NM_022469.4:c.7T>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_022469.4(GREM2):​c.7T>G​(p.Trp3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,603,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GREM2 NM_022469.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.073221475).
• BS2: High AC in GnomAd4 at 16 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GREM2	NM_022469.4	c.7T>G	p.Trp3Gly	missense_variant	Exon 2 of 2	ENST00000318160.5	NP_071914.3
GREM2	XM_047427832.1	c.61T>G	p.Trp21Gly	missense_variant	Exon 3 of 3		XP_047283788.1
GREM2	XM_047427839.1	c.61T>G	p.Trp21Gly	missense_variant	Exon 4 of 4		XP_047283795.1
GREM2	XM_011544249.3	c.7T>G	p.Trp3Gly	missense_variant	Exon 3 of 3		XP_011542551.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GREM2	ENST00000318160.5	c.7T>G	p.Trp3Gly	missense_variant	Exon 2 of 2	1	NM_022469.4	ENSP00000318650.4

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000209 AC: 49 AN: 234710 Hom.: 0 AF XY: 0.000195 AC XY: 25 AN XY: 128138

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000181

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000121 AC: 175 AN: 1451552 Hom.: 0 Cov.: 30 AF XY: 0.000141 AC XY: 102 AN XY: 721004

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000115

Gnomad4 ASJ exome AF: 0.00337

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000524

Gnomad4 OTH exome AF: 0.000417

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000521 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7T>G (p.W3G) alteration is located in exon 2 (coding exon 1) of the GREM2 gene. This alteration results from a T to G substitution at nucleotide position 7, causing the tryptophan (W) at amino acid position 3 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.050	T
Polyphen		0.44	B
Vest4		0.66
MutPred		0.54		Gain of disorder (P = 0.0051);
MVP		0.56
MPC		2.5
ClinPred		0.096	T
GERP RS		4.2
Varity_R		0.13
gMVP		0.81

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: rs201326333; hg19: chr1-240656769;