rs104894003

chr7-5528536-G-Achr7-5528536-G-Cchr7-5528536-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 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 19 ACMG points.

• PM1: In a helix (size 12) in uniprot entity ACTB_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr7-5528536-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 989344.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ACTB
• 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/exons	MANE	UniProt
ACTB	NM_001101.5	c.547C>T	p.Arg183Trp	missense_variant	4/6	ENST00000646664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTB	ENST00000646664.1	c.547C>T	p.Arg183Trp	missense_variant	4/6		NM_001101.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 70

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jun 13, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Dec 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
not provided, no classification provided	literature only	GeneReviews	-	Associated with the BWCFF syndrome phenotype with early onset, progressive dystonia, and progressive esophageal achalasia. -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	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. -

Baraitser-Winter syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jan 11, 2019	PS2, PM2, PP2, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2017

- -

ACTB-related BAFopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 10, 2021

- -

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
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;.;.
MutationTaster	Benign	1.0	A
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;