7-5529217-C-T

Position:

• chr7-5529217-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP2 PP3

The NM_001101.5(ACTB):​c.307G>A​(p.Val103Met) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V103L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-5529217-C-G is described in Lovd as [Pathogenic].
• 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, 0.787

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTB	NM_001101.5	c.307G>A	p.Val103Met	missense_variant	3/6	ENST00000646664.1	NP_001092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTB	ENST00000646664.1	c.307G>A	p.Val103Met	missense_variant	3/6		NM_001101.5	ENSP00000494750.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2018

The V103M variant in the ACTB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V103M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V103M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (V103L) has been reported in the heterozygous state in an individual diagnosed with Baraitser-Winter Cerebrofrontofacial syndrome, supporting the functional importance of this region of the protein (Verloes et al., 2015). Therefore, we interpret V103M as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D;D;.;.;D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	.;.;T;T;T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.9	N;.;.;.;.;N
REVEL	Pathogenic	0.72
Sift4G	Uncertain	0.029	D;.;.;.;.;.
Polyphen		0.48	P;P;P;.;.;.
Vest4		0.85
MutPred		0.29		Gain of catalytic residue at V103 (P = 0.0222);Gain of catalytic residue at V103 (P = 0.0222);Gain of catalytic residue at V103 (P = 0.0222);Gain of catalytic residue at V103 (P = 0.0222);Gain of catalytic residue at V103 (P = 0.0222);Gain of catalytic residue at V103 (P = 0.0222);
MVP		0.94
MPC		1.8
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.86
gMVP		0.96

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: rs587779772; hg19: chr7-5568848;