17-81510698-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001614.5(ACTG1):​c.1120T>A​(p.Cys374Ser) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C374Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ACTG1
NM_001614.5 missense

Scores

12
4
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.85

Publications

0 publications found
Variant links:
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]
ACTG1 Gene-Disease associations (from GenCC):
  • Baraitser-winter syndrome 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
  • nonsyndromic genetic hearing loss
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • autosomal dominant nonsyndromic hearing loss 20
    Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
  • autosomal dominant nonsyndromic hearing loss
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Baraitser-Winter cerebrofrontofacial syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACTG1NM_001614.5 linkc.1120T>A p.Cys374Ser missense_variant Exon 6 of 6 ENST00000573283.7 NP_001605.1 P63261
ACTG1NM_001199954.3 linkc.1120T>A p.Cys374Ser missense_variant Exon 6 of 6 NP_001186883.1 P63261
ACTG1NR_037688.3 linkn.1192T>A non_coding_transcript_exon_variant Exon 6 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACTG1ENST00000573283.7 linkc.1120T>A p.Cys374Ser missense_variant Exon 6 of 6 5 NM_001614.5 ENSP00000458435.1 P63261

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Dec 09, 2024
GeneDx
Significance:Uncertain significance
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 a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
27
DANN
Benign
0.93
DEOGEN2
Pathogenic
0.92
D;D;D;D;D;D
Eigen
Pathogenic
0.77
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Pathogenic
1.0
.;.;D;.;.;.
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.0
M;M;M;M;M;M
PhyloP100
8.9
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.6
.;D;.;.;.;.
REVEL
Pathogenic
0.96
Sift4G
Uncertain
0.010
D;D;D;D;D;.
Polyphen
0.96
D;D;D;D;D;D
Vest4
0.94
MutPred
0.87
Gain of disorder (P = 0.0103);Gain of disorder (P = 0.0103);Gain of disorder (P = 0.0103);Gain of disorder (P = 0.0103);Gain of disorder (P = 0.0103);Gain of disorder (P = 0.0103);
MVP
0.98
ClinPred
0.98
D
GERP RS
3.9
Varity_R
0.97
gMVP
0.94
Mutation Taster
=25/75
disease causing

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

Other links and lift over

hg19: chr17-79477724; API