rs144849143

Positions:

• chr3-38479666-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000352511.5(ACVR2B):​c.811-12G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,614,036 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (14 hom.)
• Consequence: ACVR2B ENST00000352511.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001156
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.31

Genes affected

ACVR2B (HGNC:174): (activin A receptor type 2B) Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF-beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I (I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. Type II receptors are considered to be constitutively active kinases. This gene encodes activin A type IIB receptor, which displays a 3- to 4-fold higher affinity for the ligand than activin A type II receptor. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-38479666-G-A is Benign according to our data. Variant chr3-38479666-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38479666-G-A is described in Lovd as [Benign]. Variant chr3-38479666-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 437 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR2B	NM_001106.4	c.811-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000352511.5	NP_001097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACVR2B	ENST00000352511.5	c.811-12G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001106.4	ENSP00000340361	P1
ACVR2B	ENST00000461232.1	n.4600-12G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
ACVR2B	ENST00000465020.5	n.897-12G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152172 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00454

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00313 AC: 786 AN: 251432 Hom.: 1 AF XY: 0.00308 AC XY: 418 AN XY: 135888

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00767

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00392 AC: 5726 AN: 1461746 Hom.: 14 Cov.: 35 AF XY: 0.00383 AC XY: 2788 AN XY: 727178

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00886

Gnomad4 NFE exome AF: 0.00435

Gnomad4 OTH exome AF: 0.00326

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152290 Hom.: 3 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74458

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.00454

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00380 Hom.: 0

Bravo AF: 0.00224

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs144849143; hg19: chr3-38521157;