chr3-38479665-T-C

Position:

• chr3-38479665-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001106.4(ACVR2B):​c.811-13T>C 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 0.527 in 1,612,976 control chromosomes in the GnomAD database, including 232,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (16310 hom., cov: 31)
  • Exomes 𝑓: 0.54 (216073 hom.)
• Consequence: ACVR2B NM_001106.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.35

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-38479665-T-C is Benign according to our data. Variant chr3-38479665-T-C is described in ClinVar as [Benign]. Clinvar id is 257470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-38479665-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACVR2B	NM_001106.4	c.811-13T>C		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.811-13T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001106.4	ENSP00000340361	P1
ACVR2B	ENST00000461232.1	n.4600-13T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
ACVR2B	ENST00000465020.5	n.897-13T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65343 AN: 151940 Hom.: 16310 Cov.: 31

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.453

GnomAD3 exomes AF: 0.478 AC: 119884 AN: 250868 Hom.: 30833 AF XY: 0.492 AC XY: 66667 AN XY: 135564

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.506

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.520

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.572

Gnomad OTH exome AF: 0.501

GnomAD4 exome AF: 0.537 AC: 783894 AN: 1460916 Hom.: 216073 Cov.: 45 AF XY: 0.538 AC XY: 390834 AN XY: 726762

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.520

Gnomad4 FIN exome AF: 0.541

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.504

GnomAD4 genome AF: 0.430 AC: 65352 AN: 152060 Hom.: 16310 Cov.: 31 AF XY: 0.427 AC XY: 31711 AN XY: 74304

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.531

Gnomad4 NFE AF: 0.573

Gnomad4 OTH AF: 0.453

Alfa AF: 0.492 Hom.: 3844

Bravo AF: 0.404

Asia WGS AF: 0.404 AC: 1403 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.0
DANN	Benign	0.70

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: rs13097628; hg19: chr3-38521156;