7-5528536-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001101.5(ACTB):​c.547C>G​(p.Arg183Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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 11 ACMG points.

• 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-A is described in Lovd as [Pathogenic].
• 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, 0.973
• PP5: Variant 7-5528536-G-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTB	NM_001101.5	c.547C>G	p.Arg183Gly	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>G	p.Arg183Gly	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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

ACTB-related disorder Pathogenic:1

Jul 30, 2019

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACTB c.547C>G (p.Arg183Gly) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. A different variant affecting the same amino acid residue, p.Arg183Trp, has been reported in at least seven individuals with dystonia, hearing loss and variable additional features (Skogseid et al. 2018). Based on the identification of the variant in a de novo state, its rarity, and literature evidence, the p.Arg183Gly variant is classified as likely pathogenic for ACTB-related disorders. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;.;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H;H;H;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.4	D;.;.;.;.
REVEL	Pathogenic	0.86
Sift4G	Uncertain	0.021	D;.;.;.;.
Polyphen		0.96	D;D;D;.;.
Vest4		0.91
MutPred		0.86		Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);Loss of stability (P = 0.0523);.;.;
MVP		0.98
MPC		3.7
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;