NM_001101.5:c.625G>A

Variant names:

• chr7-5528458-C-T
• rs587779777
• NM_001101.5:c.625G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001101.5(ACTB):​c.625G>A​(p.Val209Met) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V209L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTB NM_001101.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.62
• Publications: 9 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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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 chr7-5528458-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1700136.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.85
• PP5: Variant 7-5528458-C-T is Pathogenic according to our data. Variant chr7-5528458-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 127172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTB	NM_001101.5	c.625G>A	p.Val209Met	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.625G>A	p.Val209Met	missense_variant	Exon 4 of 6		NM_001101.5	ENSP00000494750.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baraitser-Winter syndrome 1 Pathogenic:5

Jun 19, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2014

Department of Genetics, Robert DEBRE University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 02, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2024

Daryl Scott Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PS4, PM2, PP3 -

not provided Pathogenic:3

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTB: PS2, PM2, PS4:Moderate, PP2, PP3 -

Aug 28, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously as V209L, with the same nucleotide change, in an individual with BWCFF who developed acute lymphoblastic leukemia at age eight (PMID: 25052316); Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28191890, 30733661, 28991257, 32860008, 34906496, 31941532, 25052316, 32368696) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

May 23, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.625G>A (p.V209M) alteration is located in exon 4 (coding exon 3) of the ACTB gene. This alteration results from a G to A substitution at nucleotide position 625, causing the valine (V) at amino acid position 209 to be replaced by a methionine (M)._x000D_ _x000D_ The ACTB c.625G>A (p.V209M) alteration is classified as pathogenic for Baraitser-Winter syndrome; however, its clinical significance for ACTB-related pleiotropic malformation syndrome is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration, also referred to as c.625G>A (p.V209L), was reported in multiple individuals with features consistent with Baraitser-Winter syndrome (Verloes, 2015; Bertoli-Avella, 2021), including an individual with a de novo occurrence (Jin, 2017; Edwards, 2020; Gonzalez-Teran, 2022). 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). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

ACTB-related BAFopathy Pathogenic:1

Jun 10, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.89	D;D;D;.;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;.;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.3	N;.;.;.;.
REVEL	Pathogenic	0.91
Sift4G	Uncertain	0.0080	D;.;.;.;.
Polyphen		0.039	B;B;B;.;.
Vest4		0.90
MutPred		0.73		Gain of disorder (P = 0.1232);Gain of disorder (P = 0.1232);Gain of disorder (P = 0.1232);.;.;
MVP		0.91
MPC		1.8
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.96
Mutation Taster		=5/95	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: rs587779777; hg19: chr7-5568089;