rs587779770

chr7-5529304-C-T

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.220G>A(p.Gly74Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G74C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.96

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr7-5529304-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2445203.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, ACTB
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 7-5529304-C-T is Pathogenic according to our data. Variant chr7-5529304-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-5529304-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTB	NM_001101.5	c.220G>A	p.Gly74Ser	missense_variant	3/6	ENST00000646664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTB	ENST00000646664.1	c.220G>A	p.Gly74Ser	missense_variant	3/6		NM_001101.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baraitser-Winter syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 31, 2020	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Baraitser–Winter cerebrofrontofacial syndrome (PMID: 23756437, 25052316). In at least one individual the variant was observed to be de novo (https://pdfs.semanticscholar.org/7b2e/c13a69c23df9fd91cf13024050f4d668845b.pdf). ClinVar contains an entry for this variant (Variation ID: 127163). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 74 of the ACTB protein (p.Gly74Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -
Pathogenic, no assertion criteria provided	clinical testing	Department of Genetics, Robert DEBRE University Hospital	Apr 15, 2014	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 03, 2016

The G74S missense variant in the ACTB gene has been previously published in association with Baraitser-Winter syndrome (DiDonato et al., 2014) and as de novo in the overlapping condition Fryns-Aftimos syndrome (Namiranian et al., 2015), with limited data to fully support pathogenicity. The G74S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G74S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (P70L, I75T) have been reported in the Human Gene Mutation Database in association with Baraitser-Winter syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	27
Dann	Benign	0.97
DEOGEN2	Pathogenic	0.91	D;D;D;.;.;D;D;.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;D;D;.;D
REVEL	Pathogenic	0.97
Sift4G	Uncertain	0.040	D;.;.;.;.;.;.;.;.
Polyphen		0.21	B;B;B;.;.;.;.;.;.
Vest4		0.94
MutPred		0.86		Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);Loss of catalytic residue at P70 (P = 0.0776);
MVP		0.99
MPC		3.2
ClinPred		0.99	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587779770; hg19: chr7-5568935;