rs1554329352

Positions:

• chr7-5528677-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001101.5(ACTB):​c.406A>G​(p.Ile136Val) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTB. . Trascript score misZ 7.6852 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTB	NM_001101.5	c.406A>G	p.Ile136Val	missense_variant	4/6	ENST00000646664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTB	ENST00000646664.1	c.406A>G	p.Ile136Val	missense_variant	4/6		NM_001101.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;D;D;.;.;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;.;D;D;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.7	L;L;L;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.72	N;.;.;.;.;N
REVEL	Pathogenic	0.74
Sift4G	Benign	0.14	T;.;.;.;.;.
Polyphen		0.95	P;P;P;.;.;.
Vest4		0.51
MutPred		0.71		Gain of phosphorylation at Y133 (P = 0.2183);Gain of phosphorylation at Y133 (P = 0.2183);Gain of phosphorylation at Y133 (P = 0.2183);.;Gain of phosphorylation at Y133 (P = 0.2183);Gain of phosphorylation at Y133 (P = 0.2183);
MVP		0.91
MPC		1.5
ClinPred		0.85	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.90

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: rs1554329352; hg19: chr7-5568308;