rs1554329352

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_001101.5(ACTB):​c.406A>G​(p.Ile136Val) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ACTB
NM_001101.5 missense

Scores

7
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86
Variant links:
Genes affected
ACTB (HGNC:132): (actin beta) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a major constituent of the contractile apparatus and one of the two nonmuscle cytoskeletal actins that are ubiquitously expressed. Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients. Numerous pseudogenes of this gene have been identified throughout the human genome. [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001101.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTB. . Trascript score misZ 7.6852 (greater than threshold 3.09). GenCC has associacion of gene with ACTB-associated syndromic thrombocytopenia, Baraitser-Winter cerebrofrontofacial syndrome, developmental malformations-deafness-dystonia syndrome, Baraitser-Winter syndrome 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACTBNM_001101.5 linkuse as main transcriptc.406A>G p.Ile136Val missense_variant 4/6 ENST00000646664.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACTBENST00000646664.1 linkuse as main transcriptc.406A>G p.Ile136Val missense_variant 4/6 NM_001101.5 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
66
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 17, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.67
D;D;D;.;.;D
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
.;.;D;D;D;D
M_CAP
Uncertain
0.097
D
MetaRNN
Pathogenic
0.77
D;D;D;D;D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Benign
1.7
L;L;L;.;.;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.72
N;.;.;.;.;N
REVEL
Pathogenic
0.74
Sift4G
Benign
0.14
T;.;.;.;.;.
Polyphen
0.95
P;P;P;.;.;.
Vest4
0.51
MutPred
0.71
Gain of phosphorylation at Y133 (P = 0.2183);Gain of phosphorylation at Y133 (P = 0.2183);Gain of phosphorylation at Y133 (P = 0.2183);.;Gain of phosphorylation at Y133 (P = 0.2183);Gain of phosphorylation at Y133 (P = 0.2183);
MVP
0.91
MPC
1.5
ClinPred
0.85
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.90

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554329352; hg19: chr7-5568308; API