3-38479934-C-T

Variant names:

• chr3-38479934-C-T
• rs4407366
• NM_001106.4:c.959+108C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001106.4(ACVR2B):​c.959+108C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 1,393,412 control chromosomes in the GnomAD database, including 260,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.61 (28022 hom., cov: 31)
  • Exomes 𝑓: 0.61 (232002 hom.)
• Consequence: ACVR2B NM_001106.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.241
• Publications: 8 publications found

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]

ACVR2B Gene-Disease associations (from GenCC):

• heterotaxy, visceral, 4, autosomal

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-38479934-C-T is Benign according to our data. Variant chr3-38479934-C-T is described in ClinVar as Benign. ClinVar VariationId is 1259960.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACVR2B	NM_001106.4	c.959+108C>T		intron_variant	Intron 7 of 10	ENST00000352511.5	NP_001097.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACVR2B	ENST00000352511.5	c.959+108C>T		intron_variant	Intron 7 of 10	1	NM_001106.4	ENSP00000340361.3
ACVR2B	ENST00000461232.1	n.4748+108C>T		intron_variant	Intron 6 of 9	1
ACVR2B	ENST00000465020.5	n.1045+108C>T		intron_variant	Intron 6 of 9	2

Frequencies

GnomAD3 genomes AF: 0.606 AC: 91989 AN: 151786 Hom.: 27997 Cov.: 31

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.625

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.602

GnomAD4 exome AF: 0.610 AC: 757233 AN: 1241508 Hom.: 232002 AF XY: 0.610 AC XY: 377481 AN XY: 618884

African (AFR) AF: 0.588 AC: 16881 AN: 28704

American (AMR) AF: 0.621 AC: 21987 AN: 35390

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 13351 AN: 23998

East Asian (EAS) AF: 0.602 AC: 20969 AN: 34814

South Asian (SAS) AF: 0.605 AC: 45768 AN: 75636

European-Finnish (FIN) AF: 0.569 AC: 20637 AN: 36258

Middle Eastern (MID) AF: 0.533 AC: 2296 AN: 4304

European-Non Finnish (NFE) AF: 0.615 AC: 583546 AN: 949456

Other (OTH) AF: 0.601 AC: 31798 AN: 52948

GnomAD4 genome AF: 0.606 AC: 92072 AN: 151904 Hom.: 28022 Cov.: 31 AF XY: 0.603 AC XY: 44801 AN XY: 74248

African (AFR) AF: 0.597 AC: 24737 AN: 41414

American (AMR) AF: 0.617 AC: 9421 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1955 AN: 3472

East Asian (EAS) AF: 0.625 AC: 3218 AN: 5148

South Asian (SAS) AF: 0.609 AC: 2936 AN: 4818

European-Finnish (FIN) AF: 0.554 AC: 5835 AN: 10536

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.620 AC: 42111 AN: 67926

Other (OTH) AF: 0.600 AC: 1263 AN: 2106

Alfa AF: 0.614 Hom.: 20520

Bravo AF: 0.608

Asia WGS AF: 0.617 AC: 2142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.8
DANN	Benign	0.57
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4407366; hg19: chr3-38521425; COSMIC: COSV61702482;