7-5528497-G-A

Position:

• chr7-5528497-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001101.5(ACTB):​c.586C>T​(p.Arg196Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R196H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 3.93

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 19 ACMG points.

• PM1: In a turn (size 2) 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 chr7-5528496-C-T is described in Lovd as [Likely_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, 0.979
• PP5: Variant 7-5528497-G-A is Pathogenic according to our data. Variant chr7-5528497-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5528497-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTB	NM_001101.5	c.586C>T	p.Arg196Cys	missense_variant	4/6	ENST00000646664.1	NP_001092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTB	ENST00000646664.1	c.586C>T	p.Arg196Cys	missense_variant	4/6		NM_001101.5	ENSP00000494750	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baraitser-Winter syndrome 1 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 29600). This missense change has been observed in individual(s) with Baraitser-Winter syndrome (PMID: 22366783, 23756437, 25052316). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 196 of the ACTB protein (p.Arg196Cys). -
Pathogenic, no assertion criteria provided	clinical testing	Department of Genetics, Robert DEBRE University Hospital	Apr 15, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	2nd Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens	-	- -

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 22366783, 32506774, 23756437, 25052316, 24211661, 27625340, 30733661, 11311002) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ACTB: PM1, PM2, PM5, PS2:Moderate, PS4:Moderate, PP2, PP3 -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;D;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	.;.;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.8	H;H;H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.5	D;.;.;.;.
REVEL	Pathogenic	0.89
Sift4G	Uncertain	0.046	D;.;.;.;.
Polyphen		0.91	P;P;P;.;.
Vest4		0.95
MutPred		0.90		Loss of disorder (P = 0.0781);Loss of disorder (P = 0.0781);Loss of disorder (P = 0.0781);.;.;
MVP		1.0
MPC		3.0
ClinPred		0.99	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.98

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: rs281875333; hg19: chr7-5568128; COSMIC: COSV59317670; COSMIC: COSV59317670;