NM_001101.5:c.193C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001101.5(ACTB):​c.193C>T​(p.Leu65Phe) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L65V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

ACTB
NM_001101.5 missense

Scores

12
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.86

Publications

12 publications found
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]
ACTB Gene-Disease associations (from GenCC):
  • Baraitser-Winter cerebrofrontofacial syndrome
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • Baraitser-Winter syndrome 1
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P
  • developmental malformations-deafness-dystonia syndrome
    Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina
  • ACTB-associated syndromic thrombocytopenia
    Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001101.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-5529331-G-C is described in CliVar as Pathogenic. Clinvar id is 29601.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant in the ACTB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Trascript score misZ: 7.6852 (above the threshold of 3.09). GenCC associations: The gene is linked to Baraitser-Winter syndrome 1, developmental malformations-deafness-dystonia syndrome, Baraitser-Winter cerebrofrontofacial syndrome, ACTB-associated syndromic thrombocytopenia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.944
PP5
Variant 7-5529331-G-A is Pathogenic according to our data. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529331-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 127161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTBNM_001101.5 linkc.193C>T p.Leu65Phe missense_variant Exon 3 of 6 ENST00000646664.1 NP_001092.1 P60709Q1KLZ0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTBENST00000646664.1 linkc.193C>T p.Leu65Phe missense_variant Exon 3 of 6 NM_001101.5 ENSP00000494750.1 P60709

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Baraitser-Winter syndrome 1 Pathogenic:2
Feb 12, 2024
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

A heterozygous missense variant in exon 3 of the ACTB gene that results in the amino acid substitution of Phenylalanine for Leucine at codon 65 (p.Leu65Phe) was detected. The observed variant and a different missense in the same codon (p.Leu65Val) has previously been reported in patients affected with Baraitser-Winter syndrome [PMID: 25052316, ClinVar: VCV000127161.4]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv), SIFT and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a likely pathogenic. -

Apr 15, 2014
Department of Genetics, Robert DEBRE University Hospital
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not provided Pathogenic:1
Jul 10, 2024
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Identified in multiple patients with features of ACTB-related Baraitser-Winter syndrome in published literature and tested at GeneDx, reported de novo with or without confirmed parentage when parental samples were available (PMID: 38444904, 25052316); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22366783, 38444904, 25052316) -

Intellectual disability Pathogenic:1
Dec 01, 2018
Diagnostic Laboratory, Strasbourg University Hospital
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.88
D;D;D;.;.;D;D;.;D
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.97
.;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.94
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;H;H;.;.;.;.;.;.
PhyloP100
7.9
PrimateAI
Pathogenic
0.88
D
PROVEAN
Uncertain
-2.4
N;.;.;.;.;D;D;.;D
REVEL
Pathogenic
0.98
Sift4G
Uncertain
0.0040
D;.;.;.;.;.;.;.;.
Polyphen
1.0
D;D;D;.;.;.;.;.;.
Vest4
0.95
MutPred
0.78
Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);Gain of ubiquitination at K61 (P = 0.1062);
MVP
0.98
MPC
3.3
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.98
gMVP
0.96
Mutation Taster
=21/79
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs281875332; hg19: chr7-5568962; COSMIC: COSV100079766; COSMIC: COSV100079766; API