rs1333150865

Variant names:

• chr12-51982736-G-A
• rs1333150865
• NM_004302.5:c.812-1263G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51982736-G-A
• chr12-51982736-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_020328.4(ACVR1B):​c.862G>A​(p.Ala288Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000724 in 1,382,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A288S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ACVR1B NM_020328.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0100
• Publications: 0 publications found

Genes affected

ACVR1B (HGNC:172): (activin A receptor type 1B) This gene encodes an activin A type IB receptor. 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 and two type II receptors. This protein is a type I receptor which is essential for signaling. Mutations in this gene are associated with pituitary tumors. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010]

ACVR1B Gene-Disease associations (from GenCC):

• malignant pancreatic neoplasm

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.3735 (above the threshold of 3.09). Trascript score misZ: 4.4731 (above the threshold of 3.09). GenCC associations: The gene is linked to malignant pancreatic neoplasm.
• BP4: Computational evidence support a benign effect (MetaRNN=0.097135484).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020328.4. 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
	ACVR1B	NM_004302.5	MANE Select	c.812-1263G>A		intron	N/A	NP_004293.1	P36896-1
	ACVR1B	NM_020328.4		c.862G>A	p.Ala288Thr	missense	Exon 5 of 10	NP_064733.3
	ACVR1B	NM_001412774.1		c.859G>A	p.Ala287Thr	missense	Exon 5 of 10	NP_001399703.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1B	ENST00000257963.9	TSL:1 MANE Select	c.812-1263G>A		intron	N/A	ENSP00000257963.4	P36896-1
	ACVR1B	ENST00000541224.5	TSL:2	c.862G>A	p.Ala288Thr	missense	Exon 5 of 10	ENSP00000442656.1	P36896-4
	ACVR1B	ENST00000900350.1		c.859G>A	p.Ala287Thr	missense	Exon 5 of 10	ENSP00000570409.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1382018 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 681930

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000317 AC: 1 AN: 31546

American (AMR) AF: 0.00 AC: 0 AN: 35476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25146

East Asian (EAS) AF: 0.00 AC: 0 AN: 35588

South Asian (SAS) AF: 0.00 AC: 0 AN: 78802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078040

Other (OTH) AF: 0.00 AC: 0 AN: 57848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.7
DANN	Benign	0.97
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.37	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.36	T
PhyloP100		0.010
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.096
Sift	Benign	0.14	T
Sift4G	Benign	0.69	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.41		Gain of catalytic residue at V285 (P = 0.0086)
MVP		0.64
MPC		0.97
ClinPred		0.058	T
GERP RS		0.68
gMVP		0.18
Mutation Taster		=97/3	polymorphism

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: rs1333150865; hg19: chr12-52376520;