NM_001101.5:c.209C>T

Variant names:

• chr7-5529315-G-A
• rs587779769
• NM_001101.5:c.209C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001101.5(ACTB):​c.209C>T​(p.Pro70Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P70H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 9.72
• Publications: 4 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 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001101.5
• 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 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, 0.982
• PP5: Variant 7-5529315-G-A is Pathogenic according to our data. Variant chr7-5529315-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127162.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTB	NM_001101.5	c.209C>T	p.Pro70Leu	missense_variant	Exon 3 of 6	ENST00000646664.1	NP_001092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTB	ENST00000646664.1	c.209C>T	p.Pro70Leu	missense_variant	Exon 3 of 6		NM_001101.5	ENSP00000494750.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Baraitser-Winter syndrome 1 Pathogenic:2 Uncertain:1

Aug 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 70 of the ACTB protein (p.Pro70Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Baraister-Winter syndrome (PMID: 25052316, 26275891). ClinVar contains an entry for this variant (Variation ID: 127162). 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 expected to disrupt ACTB protein function with a positive predictive value of 80%. This variant disrupts the p.Pro70 amino acid residue in ACTB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 30733661). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 15, 2014

Department of Genetics, Robert DEBRE University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 17, 2023

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: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ACTB-related neurodevelopmental disorder. However, gain of function, dominant negative and loss of function are suggested mechanisms for variants associated with Baraitser-Winter syndrome (MIM#243310; PMID: 29220674). The mechanism of juvenile-onset dystonia (MIM#607371) is unclear. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. High clinical variability has been observed between individuals with Baraitser-Winter syndrome who harbour the same variant (PMID: 26583190, PMID: 30315159). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (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) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. This alternative change (p.(Pro70Ala)) has been reported as de novo in an individual with Baraitser-Winter syndrome (BWS; PMID: 30733661). Another comparable variant (p.(Pro70His)) has been reported as a VUS (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed twice as de novo, and reported as pathogenic and likely pathogenic in an additional three unrelated individuals with BWS (LOVD, VCGS, ClinVar, PMID: 26275891, PMID: 25052316). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:2

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in unrelated patients with ACTB-related clinical features referred for genetic testing at GeneDx and in published literature (PMID: 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: 37500730, 25052316, 26275891) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;D;.;.;D;D;.;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	.;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H;H;.;.;.;.;.;.
PhyloP100		9.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.0	D;.;.;.;.;D;D;.;D
REVEL	Pathogenic	0.98
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.
Polyphen		0.023	B;B;B;.;.;.;.;.;.
Vest4		0.98
MutPred		0.87		Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);Gain of ubiquitination at K68 (P = 0.0918);
MVP		0.99
MPC		3.2
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.96
gMVP		1.0
Mutation Taster		=1/99	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: rs587779769; hg19: chr7-5568946;