7-5527770-A-ATGGAGGGGCCGGAC

Position:

• chr7-5527770-A-ATGGAGGGGCCGGAC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001101.5(ACTB):​c.1105_1106insGTCCGGCCCCTCCA​(p.Ile369SerfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. I369I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTB NM_001101.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.73

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0204 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-5527770-A-ATGGAGGGGCCGGAC is Pathogenic according to our data. Variant chr7-5527770-A-ATGGAGGGGCCGGAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373015.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTB	NM_001101.5	c.1105_1106insGTCCGGCCCCTCCA	p.Ile369SerfsTer18	frameshift_variant	6/6	ENST00000646664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTB	ENST00000646664.1	c.1105_1106insGTCCGGCCCCTCCA	p.Ile369SerfsTer18	frameshift_variant	6/6		NM_001101.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2016

The c.1092_1105dup14 likely pathogenic variant in the ACTB gene has not been reported previouslyas a pathogenic variant nor as a benign variant, to our knowledge. The c.1092_1105dup14 variantcauses a frameshift starting with codon Isoleucine 369, changes this amino acid to a Serine residue, andcreates a Stop codon at position 18 of the new reading frame, denoted p.Ile369SerfsX18 . This variantreplaces the usual last seven amino acids of the protein with 17 incorrect amino acids, elongating theprotein. This elongated protein may result in a gain-of-function, as observed with other ACTB genevariants resulting in Baraitser-Winter syndrome (Riviere et al., 2012); however, in the absence offunctional studies, the impact of c.1092_1105dup14 on the resultant protein is not known. Inaddition, the c.1092_1105dup14 variant was not observed in approximately 6,500 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. Therefore, we interpret c.1092_1105dup14 as a likelypathogenic variant and as a possible explanation for growth retardation, developmentaldelays, short stature, corectopia, unusual stroma of the irides, facial dysmorphism, and intellectualdisability. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518142; hg19: chr7-5567401;