rs774670389

Variant names:

• chr12-51993995-T-A
• rs774670389
• NM_004302.5:c.1403T>A

Your query was ambiguous. Multiple possible variants found:

• chr12-51993995-T-A
• chr12-51993995-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_004302.5(ACVR1B):​c.1403T>A​(p.Val468Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. V468G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACVR1B NM_004302.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02
• 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 4 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: 4.5396 (above the threshold of 3.09). GenCC associations: The gene is linked to malignant pancreatic neoplasm.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004302.5. 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.1403T>A	p.Val468Glu	missense	Exon 9 of 9	NP_004293.1	P36896-1
	ACVR1B	NM_020328.4		c.1526T>A	p.Val509Glu	missense	Exon 10 of 10	NP_064733.3
	ACVR1B	NM_001412774.1		c.1523T>A	p.Val508Glu	missense	Exon 10 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.1403T>A	p.Val468Glu	missense	Exon 9 of 9	ENSP00000257963.4	P36896-1
	ACVR1B	ENST00000541224.5	TSL:2	c.1526T>A	p.Val509Glu	missense	Exon 10 of 10	ENSP00000442656.1	P36896-4
	ACVR1B	ENST00000900350.1		c.1523T>A	p.Val508Glu	missense	Exon 10 of 10	ENSP00000570409.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.24	N
PhyloP100		8.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.55
Sift	Benign	0.31	T
Sift4G	Benign	0.92	T
Polyphen		0.96	D
Vest4		0.84
MutPred		0.49		Gain of catalytic residue at M473 (P = 2e-04)
MVP		0.88
MPC		2.6
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.66
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774670389; hg19: chr12-52387779;