17-81510814-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_001614.5(ACTG1):​c.1004G>A​(p.Arg335His) 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. R335C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

ACTG1
NM_001614.5 missense

Scores

10
5
3

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.52
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-81510815-G-A is described in Lovd as [Likely_pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTG1. . Gene score misZ 3.16 (greater than the threshold 3.09). Trascript score misZ 4.8823 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.984
PP5
Variant 17-81510814-C-T is Pathogenic according to our data. Variant chr17-81510814-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACTG1NM_001614.5 linkuse as main transcriptc.1004G>A p.Arg335His missense_variant 6/6 ENST00000573283.7 NP_001605.1 P63261
ACTG1NM_001199954.3 linkuse as main transcriptc.1004G>A p.Arg335His missense_variant 6/6 NP_001186883.1 P63261
ACTG1NR_037688.3 linkuse as main transcriptn.1076G>A non_coding_transcript_exon_variant 6/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACTG1ENST00000573283.7 linkuse as main transcriptc.1004G>A p.Arg335His missense_variant 6/65 NM_001614.5 ENSP00000458435.1 P63261

Frequencies

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

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Baraitser-winter syndrome 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testing3billionOct 02, 2021The variant has been previously reported as de novoo in a similarly affected individual (PMID: 27240540, PS2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2). Missense changes are a common disease-causing mechanism (PP2).. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.844, 3Cnet: 0.988, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterMar 07, 2022- -
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille-- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 14, 2015- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 10, 2024Not 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; This variant is associated with the following publications: (PMID: 27240540, 35054877) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.47
CADD
Uncertain
25
DANN
Benign
0.94
DEOGEN2
Pathogenic
0.93
D;D;D;D;D;D
Eigen
Uncertain
0.23
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.88
.;.;D;.;.;.
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Pathogenic
0.87
D
MutationAssessor
Pathogenic
3.9
H;H;H;H;H;H
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-2.9
.;D;.;.;.;.
REVEL
Pathogenic
0.84
Sift4G
Uncertain
0.048
D;D;D;D;D;.
Polyphen
0.0010
B;B;B;B;B;B
Vest4
0.91
MutPred
0.87
Loss of MoRF binding (P = 0.0499);Loss of MoRF binding (P = 0.0499);Loss of MoRF binding (P = 0.0499);Loss of MoRF binding (P = 0.0499);Loss of MoRF binding (P = 0.0499);Loss of MoRF binding (P = 0.0499);
MVP
0.98
ClinPred
0.99
D
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.91
gMVP
0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555666392; hg19: chr17-79477840; API