12-51986903-CTT-GTC

Variant names:

• chr12-51986903-CTT-GTC
• NM_004302.5:c.1222_1224delCTTinsGTC
• ACVR1B p.Leu408Val

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_004302.5(ACVR1B):​c.1222_1224delCTTinsGTC​(p.Leu408Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• 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 2 ACMG points.

• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1222_1224delCTTinsGTC	p.Leu408Val	missense	N/A	NP_004293.1	P36896-1
	ACVR1B	NM_020328.4		c.1345_1347delCTTinsGTC	p.Leu449Val	missense	N/A	NP_064733.3
	ACVR1B	NM_001412774.1		c.1342_1344delCTTinsGTC	p.Leu448Val	missense	N/A	NP_001399703.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1B	ENST00000257963.9	TSL:1 MANE Select	c.1222_1224delCTTinsGTC	p.Leu408Val	missense	N/A	ENSP00000257963.4	P36896-1
	ACVR1B	ENST00000541224.5	TSL:2	c.1345_1347delCTTinsGTC	p.Leu449Val	missense	N/A	ENSP00000442656.1	P36896-4
	ACVR1B	ENST00000900350.1		c.1342_1344delCTTinsGTC	p.Leu448Val	missense	N/A	ENSP00000570409.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-52380687;