rs281875328

Variant names:

• chr17-81511230-G-A
• rs281875328
• NM_001614.5:c.760C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-81511230-G-A
• chr17-81511230-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001614.5(ACTG1):​c.760C>T​(p.Arg254Trp) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 0.571

Genes affected

ACTG1 (HGNC:144): (actin gamma 1) Actins are highly conserved proteins that are involved in various types of cell motility and in maintenance of the cytoskeleton. Three main groups of actin isoforms have been identified in vertebrate animals: alpha, beta, and gamma. The alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton and as mediators of internal cell motility. Actin gamma 1, encoded by this gene, is a cytoplasmic actin found in all cell types. Mutations in this gene are associated with DFNA20/26, a subtype of autosomal dominant non-syndromic sensorineural progressive hearing loss and also with Baraitser-Winter syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACTG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 48 curated benign missense variants. Gene score misZ: 3.16 (above the threshold of 3.09). Trascript score misZ: 4.8823 (above the threshold of 3.09). GenCC associations: The gene is linked to Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss, Baraitser-Winter cerebrofrontofacial syndrome, autosomal dominant nonsyndromic hearing loss 20.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 17-81511230-G-A is Pathogenic according to our data. Variant chr17-81511230-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81511230-G-A is described in Lovd as [Pathogenic]. Variant chr17-81511230-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.760C>T	p.Arg254Trp	missense_variant	Exon 4 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.760C>T	p.Arg254Trp	missense_variant	Exon 4 of 6		NP_001186883.1
ACTG1	NR_037688.3	n.832C>T		non_coding_transcript_exon_variant	Exon 4 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.760C>T	p.Arg254Trp	missense_variant	Exon 4 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 10, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22366783, 28496999, 27240540) -

Aug 09, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Baraitser-winter syndrome 2 Pathogenic:2

Feb 26, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 04, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Autosomal dominant nonsyndromic hearing loss 20 Pathogenic:1

Nov 12, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 moderated, PM2 moderated, PM6 moderated, PP2 supporting, PP3 supporting -

Lissencephaly Pathogenic:1

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 Pathogenic:1

Feb 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 29589). This missense change has been observed in individual(s) with Baraitser-Winter syndrome (PMID: 22366783, 27240540). 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 tryptophan, which is neutral and slightly polar, at codon 254 of the ACTG1 protein (p.Arg254Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;D
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.083
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	.;.;D;.;.;.
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	4.9	H;H;H;H;H;H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.4	.;D;.;.;.;.
REVEL	Pathogenic	0.73
Sift4G	Uncertain	0.011	D;D;D;D;D;.
Polyphen		0.0010	B;B;B;B;B;B
Vest4		0.97
MVP		0.97
ClinPred		1.0	D
GERP RS		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs281875328; hg19: chr17-79478256;