rs28999111

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001614.5(ACTG1):c.266C>T(p.Thr89Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T89T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACTG1
NM_001614.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.44

Publications

27 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

ACTG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.962

PP5

Variant 17-81512000-G-A is Pathogenic according to our data. Variant chr17-81512000-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18315.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ACTG1	NM_001614.5 link	c.266C>T	p.Thr89Ile	missense_variant	Exon 3 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3 link	c.266C>T	p.Thr89Ile	missense_variant	Exon 3 of 6		NP_001186883.1
ACTG1	NR_037688.3 link	n.338C>T		non_coding_transcript_exon_variant	Exon 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7 link	c.266C>T	p.Thr89Ile	missense_variant	Exon 3 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 20

Pathogenic:1

Nov 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Uncertain

(source)

DANN

Benign

0.72

DEOGEN2

Pathogenic

0.89

D;D;D;D;D;D;D;D;D;D;.

Eigen

Benign

-0.078

Eigen_PC

Benign

-0.045

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

.;.;D;.;.;.;D;.;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.96

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.6

M;M;M;M;M;M;.;.;.;.;.

PhyloP100

9.4

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.8

.;D;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.78

Sift4G

Uncertain

0.052

T;T;T;T;T;.;.;.;T;T;T

Polyphen

0.0010

B;B;B;B;B;B;.;.;.;.;.

Vest4

0.90

MutPred

0.80

Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);.;Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);Gain of catalytic residue at L94 (P = 0.1045);

MVP

0.94

ClinPred

0.98

GERP RS

3.0

Varity_R

0.96

gMVP

0.94

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over