chr15-32719440-A-G

Position:

• chr15-32719440-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013372.7(GREM1):​c.-2+1279A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 152,068 control chromosomes in the GnomAD database, including 10,568 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.33 (10568 hom., cov: 32)
• Consequence: GREM1 NM_013372.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0430

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-32719440-A-G is Benign according to our data. Variant chr15-32719440-A-G is described in ClinVar as [Benign]. Clinvar id is 1257647.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GREM1	NM_013372.7	c.-2+1279A>G		intron_variant		ENST00000651154.1
GREM1	NM_001191322.2	c.-2+1279A>G		intron_variant
GREM1	NM_001191323.2	c.-2+1279A>G		intron_variant
GREM1	NM_001368719.1	c.-2+738A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GREM1	ENST00000651154.1	c.-2+1279A>G		intron_variant			NM_013372.7	P1
GREM1	ENST00000560677.5	c.-2+1279A>G		intron_variant		4
GREM1	ENST00000560830.1	c.-2+1279A>G		intron_variant		2
GREM1	ENST00000652365.1	c.-2+738A>G		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50416 AN: 151950 Hom.: 10538 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.687

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.303

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.332 AC: 50500 AN: 152068 Hom.: 10568 Cov.: 32 AF XY: 0.335 AC XY: 24933 AN XY: 74328

Gnomad4 AFR AF: 0.553

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.686

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.206

Gnomad4 OTH AF: 0.308

Alfa AF: 0.243 Hom.: 1224

Bravo AF: 0.336

Asia WGS AF: 0.538 AC: 1870 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.8
DANN	Benign	0.44

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: rs9806137; hg19: chr15-33011641;