NM_001101.5:c.537C>G

Variant names:

• chr7-5528546-G-C
• rs797044950
• NM_001101.5:c.537C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001101.5(ACTB):​c.537C>G​(p.Asp179Glu) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D179H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.71
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Baraitser-Winter cerebrofrontofacial syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Baraitser-Winter syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia, G2P
• developmental malformations-deafness-dystonia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina
• ACTB-associated syndromic thrombocytopenia

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001101.5
• 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 Baraitser-Winter syndrome 1, developmental malformations-deafness-dystonia syndrome, Baraitser-Winter cerebrofrontofacial syndrome, ACTB-associated syndromic thrombocytopenia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTB	NM_001101.5	c.537C>G	p.Asp179Glu	missense_variant	Exon 4 of 6	ENST00000646664.1	NP_001092.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTB	ENST00000646664.1	c.537C>G	p.Asp179Glu	missense_variant	Exon 4 of 6		NM_001101.5	ENSP00000494750.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baraitser-Winter syndrome 1 Uncertain:1

Apr 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces aspartic acid with glutamic acid at codon 179 of the ACTB protein (p.Asp179Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of ACTB-related conditions (PMID: 26795593). ClinVar contains an entry for this variant (Variation ID: 208776). Experimental studies have shown that this variant does not substantially affect ACTB protein function (PMID: 26713879). -

Inborn genetic diseases Uncertain:1

Aug 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.537C>G (p.D179E) alteration is located in exon 4 (coding exon 3) of the ACTB gene. This alteration results from a C to G substitution at nucleotide position 537, causing the aspartic acid (D) at amino acid position 179 to be replaced by a glutamic acid (E). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Based on internal structural analysis, the p.D179E variant is mildly destabilizing to the local structure (Ambry internal data). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D;D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;.;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.7	M;M;M;.;.
PhyloP100		1.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D;.;.;.;.
REVEL	Uncertain	0.61
Sift4G	Benign	0.076	T;.;.;.;.
Polyphen		0.99	D;D;D;.;.
Vest4		0.78
MutPred		0.88		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;
MVP		0.94
MPC		3.0
ClinPred		0.99	D
GERP RS		1.9
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.92
gMVP		0.96
Mutation Taster		=40/60	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044950; hg19: chr7-5568177;