chr7-5528496-C-T

Variant names:

• chr7-5528496-C-T
• rs281875334
• NM_001101.5:c.587G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001101.5(ACTB):​c.587G>A​(p.Arg196His) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.62
• Publications: 18 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 6 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-5528497-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 127170.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, 0.939
• PP5: Variant 7-5528496-C-T is Pathogenic according to our data. Variant chr7-5528496-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 29599.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
ACTB	NM_001101.5	c.587G>A	p.Arg196His	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.587G>A	p.Arg196His	missense_variant	Exon 4 of 6		NM_001101.5	ENSP00000494750.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baraitser-Winter syndrome 1 Pathogenic:5

Aug 22, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.82 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.95 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029599 /PMID: 22366783 /3billion dataset). The variant has been previously reported as de novo in a similarly affected individual (PMID: 22366783). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22366783). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (3billion dataset). Different missense changes at the same codon (p.Arg196Cys, p.Arg196Gly, p.Arg196Leu, p.Arg196Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029600, VCV000127170, VCV001177326, VCV001193058 /PMID: 22366783, 25052316). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Feb 26, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Dec 05, 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 histidine, which is basic and polar, at codon 196 of the ACTB protein (p.Arg196His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Baraitser-Winter syndrome (PMID: 22366783). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29599). 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%. This variant disrupts the p.Arg196 amino acid residue in ACTB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366783, 23756437, 25052316). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Apr 08, 2025

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This ACTB variant is absent from a large population dataset and has been reported in ClinVar. This variant has been identified in multiple individuals diagnosed with Baraister-Winter syndrome and has been determined to be the result of a de novo change in at least three individuals. Of three bioinformatics tools queried, one predicts that the substitution (p.Arg196His) would be damaging, while two predicts that it would be tolerated. However, these algorithms have low specificity, especially for predicting gain of function variants. The arginine residue at this position is strongly conserved across the vertebrate species assessed, and another alteration at the same codon (p.Arg196Cys) has been reported in individuals with clinical features consistent with Baraister-Winter syndrome. We consider c.587G>A to be pathogenic for autosomal dominant Baraitser-Winter syndrome-1.

Jun 05, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:2 Other:1

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jun 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 05, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27868373, 22366783, 27625340, 25052316, 27096712, 10928857, 32234145)

Inborn genetic diseases Pathogenic:1

Feb 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.587G>A (p.R196H) alteration is located in exon 4 (coding exon 3) of the ACTB gene. This alteration results from a G to A substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 to be replaced by a histidine (H)._x000D_ _x000D_ for ACTB-related Baraitser-Winter syndrome; however, its clinical significance for ACTB-related pleiotropic malformation syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals diagnosed with Baraister-Winter syndrome and has been determined to be the result of a de novo mutation in three individuals diagnosed with Baraitser-Winter syndrome (Rivière, 2012; Cianci, 2017). Another alteration at the same codon, c.586C>T (p.R196C), has been reported in a cohort of individuals with clinical features consistent with Baraister-Winter syndrome (Rivière, 2012). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D;D;D;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
LIST_S2	Benign	0.0	.;.;T;T;T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Pathogenic	3.8	H;H;H;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D;.;.;.;.
Sift	Pathogenic	0.0	.;.;.;.;.
Sift4G	Uncertain	0.023	D;.;.;.;.
Vest4		0.87
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.96
Mutation Taster		=12/88	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

Other links and lift over

dbSNP: rs281875334; hg19: chr7-5568127; COSMIC: COSV100079763; COSMIC: COSV100079763;