NM_004302.5:c.1261+172G>C

Variant names:

• chr12-51987114-G-C
• rs34050429
• NM_004302.5:c.1261+172G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004302.5(ACVR1B):​c.1261+172G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 715,174 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACVR1B NM_004302.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.519
• 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.27276433).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1B	NM_004302.5	MANE Select	c.1261+172G>C		intron	N/A	NP_004293.1
	ACVR1B	NM_020328.4		c.1384+172G>C		intron	N/A	NP_064733.3
	ACVR1B	NM_001412774.1		c.1381+172G>C		intron	N/A	NP_001399703.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACVR1B	ENST00000257963.9	TSL:1 MANE Select	c.1261+172G>C		intron	N/A	ENSP00000257963.4
	ACVR1B	ENST00000415850.6	TSL:2	c.1433G>C	p.Arg478Pro	missense	Exon 7 of 7	ENSP00000397550.2
	ACVR1B	ENST00000541224.5	TSL:2	c.1384+172G>C		intron	N/A	ENSP00000442656.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 1 AN: 715174 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 378518

African (AFR) AF: 0.00 AC: 0 AN: 18586

American (AMR) AF: 0.00 AC: 0 AN: 35726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20978

East Asian (EAS) AF: 0.00 AC: 0 AN: 33744

South Asian (SAS) AF: 0.00 AC: 0 AN: 67612

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4390

European-Non Finnish (NFE) AF: 0.00000223 AC: 1 AN: 448300

Other (OTH) AF: 0.00 AC: 0 AN: 35588

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	4.0
DANN	Benign	0.63
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.23	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.52
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.16
MutPred		0.71		Gain of catalytic residue at F480 (P = 0.0092)
MVP		0.56
ClinPred		0.16	T
GERP RS		0.36
Mutation Taster		=94/6	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: rs34050429; hg19: chr12-52380898;