rs104894003

Variant names:

• chr7-5528536-G-A
• rs104894003
• NM_001101.5:c.547C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5528536-G-A
• chr7-5528536-G-C
• chr7-5528536-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001101.5(ACTB):​c.547C>T​(p.Arg183Trp) variant causes a missense change. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 6.46

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 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, 0.986
• PP5: Variant 7-5528536-G-A is Pathogenic according to our data. Variant chr7-5528536-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5528536-G-A is described in Lovd as [Pathogenic]. Variant chr7-5528536-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTB	NM_001101.5	c.547C>T	p.Arg183Trp	missense_variant	Exon 4 of 6	ENST00000646664.1	NP_001092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTB	ENST00000646664.1	c.547C>T	p.Arg183Trp	missense_variant	Exon 4 of 6		NM_001101.5	ENSP00000494750.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental malformations-deafness-dystonia syndrome Pathogenic:6 Other:1

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Complex loss of function and gain of function are known mechanisms of disease in this gene associated with dystonia (MIM#607371). Additionally, dominant-negative has also been suggested (PMIDs: 25255767, 16685646). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated N-terminally processed cytplasmic 1 actin chain (UniProt). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has consistently been reported in individuals with dystonia, bilateral hearing loss and/or intellectual disability and has been classified as pathogenic by clinical diagnostic laboratories (PMIDs: 16685646, 28487785, 29788902, 33446253, 30315159; ClinVar). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Patient EBV-transformed lymphoblastoid cells demonstrated defects in cell morphology, less effective depolymerisation of actin cytoskeleton and resistance to lactrunculin A, an actin-monomer sequestering drug, compared control lymphoblastoid cells (PMID: 16685646). (SP) 1207 - Parental origin of the variant is unresolved. While the proband’s mother tested negative for the variant, it should be noted that the proband’s deceased father has not been tested for the variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Associated with the BWCFF syndrome phenotype with early onset, progressive dystonia, and progressive esophageal achalasia. -

Feb 26, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.547C>T;p.(Arg183Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 18275; PMID: 26583190;16685646; 28487785; 29788902; 31970217) - PS4. This variant is not present in population databases (rs104894003, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 16685646; 28487785; 29788902) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Jun 13, 2019

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change is predicted to replace arginine with tryptophan at codon 183 of the ACTB protein (p.Arg183Trp). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the ATP-binding pocket region (PMID: 16685646). There is a large physicochemical difference between arginine and tryptophan. The variant is absent in a large population cohort (PM2; gnomAD v2.1). The variant is recurrent and has been reported in at least six probands with dystonia and sensorineural deafness, including two assumed de novo occurrences (PS4_Supporting, PM6_Strong; PMID: 16685646, 27862284, 28487785, 28849312, 29788902, 31970217). The variant results in altered protein confirmation causing decreased polymerization rates in in vitro functional assays and assessment of patient cells (PS3_Supporting, PP4; PMID: 16685646, 25255767). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 6/7 algorithms). In addition, ACTB is a gene with a low rate of benign missense variation and missense variants are a common mechanism of disease (PP2; gnomAD v2.1 gene missense constraint). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM6_Strong, PM2, PS3_Supporting, PS4_Supporting, PP2, PP3, PP4. -

Dec 07, 2022

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Baraitser-Winter syndrome 1 Pathogenic:4

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the ACTB protein (p.Arg183Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ACTB-related dystonia (PMID: 16685646, 28849312, 33446253). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 18275). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACTB function (PMID: 16685646). For these reasons, this variant has been classified as Pathogenic. -

Jan 11, 2019

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM2, PP2, PP3, PP4, PP5 -

Sep 27, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) at coding position 547 of the ACTB gene that results in an arginine to tryptophan amino acid change at residue 183 of the ACTB-encoded protein, beta-actin. The Arg183 residue falls in the ATP-binding pocket region which plays a critical role in the polymerization of beta-actin into filaments (PMID: 16685646). This is a previously reported variant (ClinVar) that has been observed in heterozygous individuals affected by dystonia-deafness syndrome (PMID: 31970217, 29788902, 28849312, 28487785, 16685646). In addition, this variant has been observed co-segregating with this disorder in at least one family (PMID: 2786228). This variant is absent from the gnomAD control population dataset (0 of approximately 250,000 alleles). Multiple bioinformatic tools predict that this arginine to tryptophan amino acid change would disrupt the beta-actin structure and/or function, and the Arg183 residue is strongly conserved across the vertebrate species examined. Functiol studies have demonstrated that the protein generated by the variant is impaired in forming long, stable filaments, and its interaction with myosin is disrupted (PMID: 16685646, 25255767). Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PP2, PP3, PS3, PS4 -

not provided Pathogenic:2

Oct 05, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies demonstrate that the R183W variant results in altered protein confirmation causing decreased polymerization rates as compared to wild type (Procaccio et al., 2006; Hundt et al., 2014); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25255767, 16685646, 28849312, 27862284, 28487785, 22366783, 27240540, 33446253, 33098801, 31970217, 29788902, 33144682, 35005077, 34008892, 26583190) -

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Apr 03, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACTB-related BAFopathy Pathogenic:1

Jun 10, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	33
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.96	D;D;D;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;.;D;D;T
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	D;.;.;.;.
REVEL	Pathogenic	0.85
Sift4G	Uncertain	0.020	D;.;.;.;.
Polyphen		0.29	B;B;B;.;.
Vest4		0.84
MutPred		0.95		Loss of methylation at R183 (P = 0.0677);Loss of methylation at R183 (P = 0.0677);Loss of methylation at R183 (P = 0.0677);.;.;
MVP		0.97
MPC		3.3
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.94
gMVP		0.98

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

Other links and lift over

dbSNP: rs104894003; hg19: chr7-5568167;