chr3-38454323-A-G

Variant names:

• chr3-38454323-A-G
• rs1559642966
• NM_001106.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001106.4(ACVR2B):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACVR2B NM_001106.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72
• Publications: 0 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-AS1 (HGNC:44161): (ACVR2B antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 159 codons. Genomic position: 38478245. Lost 0.309 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001106.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2B	NM_001106.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	NP_001097.2	Q13705-1
	ACVR2B-AS1	NR_028389.1		n.318+180T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR2B	ENST00000352511.5	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000340361.3	Q13705-1
	ACVR2B	ENST00000922132.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000592191.1
	ACVR2B	ENST00000465020.5	TSL:2	n.5A>G		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1145050 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 553726

African (AFR) AF: 0.00 AC: 0 AN: 23608

American (AMR) AF: 0.00 AC: 0 AN: 14182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17036

East Asian (EAS) AF: 0.00 AC: 0 AN: 26434

South Asian (SAS) AF: 0.00 AC: 0 AN: 36118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3138

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 954358

Other (OTH) AF: 0.00 AC: 0 AN: 45750

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Heterotaxy, visceral, 4, autosomal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.66	T
PhyloP100		1.7
PROVEAN	Benign	-0.36	N
REVEL	Uncertain	0.43
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.81
MutPred		1.0		Gain of loop (P = 0.0435)
MVP		0.97
ClinPred		0.81	D
GERP RS		1.4
PromoterAI		-0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.23
gMVP		0.63
Mutation Taster		=29/171	disease causing

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: rs1559642966; hg19: chr3-38495814;