NM_004302.5:c.35C>T

Variant names:

• chr12-51951778-C-T
• rs750134234
• NM_004302.5:c.35C>T

Variant summary

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

The NM_004302.5(ACVR1B):​c.35C>T​(p.Pro12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,295,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P12S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: ACVR1B NM_004302.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 1 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: 4.5396 (above the threshold of 3.09). GenCC associations: The gene is linked to malignant pancreatic neoplasm.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17676264).

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.35C>T	p.Pro12Leu	missense	Exon 1 of 9	NP_004293.1	P36896-1
	ACVR1B	NM_020328.4		c.35C>T	p.Pro12Leu	missense	Exon 1 of 10	NP_064733.3
	ACVR1B	NM_001412774.1		c.35C>T	p.Pro12Leu	missense	Exon 1 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.35C>T	p.Pro12Leu	missense	Exon 1 of 9	ENSP00000257963.4	P36896-1
	ACVR1B	ENST00000541224.5	TSL:2	c.35C>T	p.Pro12Leu	missense	Exon 1 of 10	ENSP00000442656.1	P36896-4
	ACVR1B	ENST00000900350.1		c.35C>T	p.Pro12Leu	missense	Exon 1 of 10	ENSP00000570409.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151206 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 8.74e-7 AC: 1 AN: 1144186 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 546758

African (AFR) AF: 0.00 AC: 0 AN: 24484

American (AMR) AF: 0.00 AC: 0 AN: 16296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14892

East Asian (EAS) AF: 0.00 AC: 0 AN: 29958

South Asian (SAS) AF: 0.00 AC: 0 AN: 24964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 945538

Other (OTH) AF: 0.00 AC: 0 AN: 45406

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151206 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73798

African (AFR) AF: 0.00 AC: 0 AN: 41252

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000198 AC: 1 AN: 5052

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67686

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.12
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.28	N
REVEL	Uncertain	0.31
Sift	Benign	0.70	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.37		Gain of catalytic residue at S8 (P = 0.0025)
MVP		0.68
MPC		1.0
ClinPred		0.091	T
GERP RS		0.44
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.036
gMVP		0.62
Mutation Taster		=76/24	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: rs750134234; hg19: chr12-52345562; COSMIC: COSV99232197; COSMIC: COSV99232197;