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rs182162229

chr17-81511336-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001614.5(ACTG1):c.654C>T(p.Tyr218=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,613,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

ACTG1
NM_001614.5 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.223
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-81511336-G-A is Benign according to our data. Variant chr17-81511336-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434076.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.223 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00023 (35/152356) while in subpopulation NFE AF= 0.000397 (27/68032). AF 95% confidence interval is 0.00028. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 35 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ACTG1NM_001614.5 linkuse as main transcriptc.654C>T p.Tyr218= synonymous_variant 4/6 ENST00000573283.7
ACTG1NM_001199954.3 linkuse as main transcriptc.654C>T p.Tyr218= synonymous_variant 4/6
ACTG1NR_037688.3 linkuse as main transcriptn.726C>T non_coding_transcript_exon_variant 4/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ACTG1ENST00000573283.7 linkuse as main transcriptc.654C>T p.Tyr218= synonymous_variant 4/65 NM_001614.5 P4

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000230
AC:
35
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000207
AC:
52
AN:
250816
Hom.:
0
AF XY:
0.000184
AC XY:
25
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.0000995
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000379
Gnomad OTH exome
AF:
0.000653
GnomAD4 exome
AF:
0.000234
AC:
342
AN:
1461524
Hom.:
0
Cov.:
37
AF XY:
0.000232
AC XY:
169
AN XY:
727084
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000113
Gnomad4 NFE exome
AF:
0.000276
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000230
AC:
35
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74508
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000366
Hom.:
0
Bravo
AF:
0.000159
EpiCase
AF:
0.000382
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Baraitser-winter syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoAug 25, 2015- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 30, 2012Tyr218Tyr in Exon 04 of ACTG1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 1/7018 European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS). -
ACTG1-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJun 09, 2020This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 24, 2021- -
Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 06, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.55
Cadd
Benign
9.6
Dann
Benign
0.95
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs182162229; hg19: chr17-79478362; API