3-38489720-T-G

Variant summary

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

The NM_001106.4(ACVR2B):c.*6388T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 152,442 control chromosomes in the GnomAD database, including 20,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.49 (20262 hom., cov: 32)
  • Exomes 𝑓: 0.54 (55 hom.)
• Consequence: ACVR2B NM_001106.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.284

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-38489720-T-G is Benign according to our data. Variant chr3-38489720-T-G is described in ClinVar as [Benign]. Clinvar id is 345010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR2B	NM_001106.4	c.*6388T>G		3_prime_UTR_variant	11/11	ENST00000352511.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR2B	ENST00000352511.5	c.*6388T>G		3_prime_UTR_variant	11/11	1	NM_001106.4	P1

Frequencies

GnomAD3 genomes AF: 0.488 AC: 74181 AN: 151920 Hom.: 20261 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.501

GnomAD4 exome AF: 0.540 AC: 218 AN: 404 Hom.: 55 Cov.: 0 AF XY: 0.561 AC XY: 137 AN XY: 244

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 0.541

Gnomad4 NFE exome AF: 0.667

Gnomad4 OTH exome AF: 0.333

GnomAD4 genome AF: 0.488 AC: 74214 AN: 152038 Hom.: 20262 Cov.: 32 AF XY: 0.488 AC XY: 36230 AN XY: 74314

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.530

Gnomad4 ASJ AF: 0.553

Gnomad4 EAS AF: 0.461

Gnomad4 SAS AF: 0.573

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.618

Gnomad4 OTH AF: 0.500

Alfa AF: 0.585 Hom.: 31571

Bravo AF: 0.470

Asia WGS AF: 0.518 AC: 1799 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	3.8
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7374458; hg19: chr3-38531211;