rs750134234

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_004302.5(ACVR1B):c.35C>A(p.Pro12His) 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 1,295,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.116

Publications

1 publications found

Variant links:

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

ACVR1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 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=0.32085222).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACVR1B	NM_004302.5	MANE Select	c.35C>A	p.Pro12His	missense	Exon 1 of 9	NP_004293.1	P36896-1
ACVR1B	NM_020328.4		c.35C>A	p.Pro12His	missense	Exon 1 of 10	NP_064733.3
ACVR1B	NM_001412774.1		c.35C>A	p.Pro12His	missense	Exon 1 of 10	NP_001399703.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACVR1B	ENST00000257963.9	TSL:1 MANE Select	c.35C>A	p.Pro12His	missense	Exon 1 of 9	ENSP00000257963.4	P36896-1
ACVR1B	ENST00000541224.5	TSL:2	c.35C>A	p.Pro12His	missense	Exon 1 of 10	ENSP00000442656.1	P36896-4
ACVR1B	ENST00000900350.1		c.35C>A	p.Pro12His	missense	Exon 1 of 10	ENSP00000570409.1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151206

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000105

AC:

AN:

95038

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000151

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

8.74e-7

AC:

AN:

1144186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

546758

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

24484

American (AMR)

AF:

0.00

AC:

AN:

16296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14892

East Asian (EAS)

AF:

0.0000334

AC:

AN:

29958

South Asian (SAS)

AF:

0.00

AC:

AN:

24964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4096

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

945538

Other (OTH)

AF:

0.00

AC:

AN:

45406

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151310

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41368

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000199

AC:

AN:

5036

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67676

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000905

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.43

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.0

PhyloP100

0.12

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.29

Sift

Benign

0.55

Sift4G

Benign

0.17

Polyphen

0.70

Vest4

0.43

MutPred

0.33

Gain of catalytic residue at S8 (P = 0.0017)

MVP

0.85

MPC

1.3

ClinPred

0.13

GERP RS

0.44

PromoterAI

-0.11

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.10

gMVP

0.59

Mutation Taster

=73/27

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over