rs121434437

chr3-38477353-G-A

Variant summary

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

The NM_001106.4(ACVR2B):c.119G>A(p.Arg40His) variant causes a missense change. The variant allele was found at a frequency of 0.000846 in 1,614,162 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (5 hom.)
• Consequence: ACVR2B NM_001106.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 4.49

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 (MetaRNN=0.009315461).
• BP6: Variant 3-38477353-G-A is Benign according to our data. Variant chr3-38477353-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 6858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 553 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACVR2B	NM_001106.4	c.119G>A	p.Arg40His	missense_variant	2/11	ENST00000352511.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACVR2B	ENST00000352511.5	c.119G>A	p.Arg40His	missense_variant	2/11	1	NM_001106.4	P1
ACVR2B	ENST00000461232.1	n.3908G>A		non_coding_transcript_exon_variant	1/10	1
ACVR2B	ENST00000465020.5	n.123G>A		non_coding_transcript_exon_variant	2/10	2

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152200 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00111 AC: 279 AN: 251194 Hom.: 2 AF XY: 0.000840 AC XY: 114 AN XY: 135784

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000555 AC: 812 AN: 1461846 Hom.: 5 Cov.: 31 AF XY: 0.000507 AC XY: 369 AN XY: 727226

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000204

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00364 AC: 554 AN: 152316 Hom.: 8 Cov.: 32 AF XY: 0.00342 AC XY: 255 AN XY: 74478

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00112 Hom.: 3

Bravo AF: 0.00454

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Heterotaxy, visceral, 4, autosomal Pathogenic:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1999	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	0.013
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0093	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.96	A
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.44
Sift	Benign	0.045	D
Sift4G	Benign	0.12	T
Polyphen		0.056	B
Vest4		0.20
MVP		0.87
MPC		1.2
ClinPred		0.031	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.56

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: rs121434437; hg19: chr3-38518844;