chr7-5527764-T-C

Variant names:

• chr7-5527764-T-C
• NM_001101.5:c.1112A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001101.5(ACTB):​c.1112A>G​(p.His371Arg) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTB NM_001101.5 missense
• 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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACTB gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Trascript score misZ: 7.6852 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.927
• PP5: Variant 7-5527764-T-C is Pathogenic according to our data. Variant chr7-5527764-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3773846.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTB	NM_001101.5	c.1112A>G	p.His371Arg	missense_variant	Exon 6 of 6	ENST00000646664.1	NP_001092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTB	ENST00000646664.1	c.1112A>G	p.His371Arg	missense_variant	Exon 6 of 6		NM_001101.5	ENSP00000494750.1

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

ACTB-related disorder Pathogenic:1

Oct 29, 2024

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ACTB gene is constrained against variation (Z-score= 7.69 and pLI = 1), and missense variation is an established mechanism of disease (HGMD, ClinVar database; PMID: 26583190). The c.1112A>G (p.His371Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a de novo heterozygous change in a patient with features of Baraitser-Winter cerebrofrontofacial syndrome including developmental delay, seizures, microcephaly, hypoplasia of the corpus callosum, and pectus excavatum (PMID: 37500730; Decipher Patient ID: 259221). The c.1112A>G (p.His371Arg) variant is absent from the latest version of the gnomAD population database and thus is presumed to be rare. Based on parental analysis, this variant likely occurred as a de novo event. Based on the available evidence, c.1112A>G (p.His371Arg) is classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	.;.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D;.;.
REVEL	Pathogenic	0.95
Sift4G	Uncertain	0.0040	D;.;.
Polyphen		0.89	P;P;P
Vest4		0.91
MutPred		0.66		Gain of MoRF binding (P = 0.0422);Gain of MoRF binding (P = 0.0422);Gain of MoRF binding (P = 0.0422);
MVP		0.99
MPC		3.5
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-5567395;