rs765265404

Positions:

• chr7-5529173-C-A
• chr7-5529173-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_001101.5(ACTB):​c.351G>T​(p.Glu117Asp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E117K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.658

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 13 ACMG points.

• PM1: In a helix (size 12) in uniprot entity ACTB_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001101.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-5529175-C-T 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, 0.964
• PP5: Variant 7-5529173-C-A is Pathogenic according to our data. Variant chr7-5529173-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 431099.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-5529173-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTB	NM_001101.5	c.351G>T	p.Glu117Asp	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.351G>T	p.Glu117Asp	missense_variant	3/6		NM_001101.5	ENSP00000494750	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Baraitser-Winter syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Aug 01, 2017

The de novo missense variant c.351G>T, p.(Glu117Asp) in ACTB was identified in a girl with severe ID, congenital heart defect, cleft lip and palate and epilepsy. At the same position, another missense variant p.(Glu117Lys) was previously reported in a patient with atypical Baraitser-Winter syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D;D;D;.;.;D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;.;D;D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	H;H;H;.;.;.
MutationTaster	Benign	0.52	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.4	N;.;.;.;.;D
REVEL	Pathogenic	0.72
Sift4G	Uncertain	0.030	D;.;.;.;.;.
Polyphen		0.99	D;D;D;.;.;.
Vest4		0.80
MutPred		0.82		Loss of ubiquitination at K118 (P = 0.0618);Loss of ubiquitination at K118 (P = 0.0618);Loss of ubiquitination at K118 (P = 0.0618);Loss of ubiquitination at K118 (P = 0.0618);Loss of ubiquitination at K118 (P = 0.0618);Loss of ubiquitination at K118 (P = 0.0618);
MVP		0.98
MPC		2.9
ClinPred		0.99	D
GERP RS		0.44
Varity_R		0.97
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: rs765265404; hg19: chr7-5568804;