chr17-81512304-G-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_001614.5(ACTG1):c.51C>G(p.Cys17Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C17Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ACTG1
NM_001614.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.23

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

ACTG1 links:

Genome browser will be placed here

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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-81512305-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 985561.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5 link	c.51C>G	p.Cys17Trp	missense_variant	Exon 2 of 6	ENST00000573283.7	NP_001605.1	P63261
ACTG1	NM_001199954.3 link	c.51C>G	p.Cys17Trp	missense_variant	Exon 2 of 6		NP_001186883.1	P63261
ACTG1	NR_037688.3 link	n.123C>G		non_coding_transcript_exon_variant	Exon 2 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7 link	c.51C>G	p.Cys17Trp	missense_variant	Exon 2 of 6	5	NM_001614.5	ENSP00000458435.1		P63261

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74462

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41550

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

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

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

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

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.88

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;H;H;H;H;H;.;.;.;.;.

PhyloP100

5.2

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-3.7

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

REVEL

Pathogenic

0.78

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.92

MutPred

0.33

Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);

MVP

0.99

ClinPred

1.0

GERP RS

2.9

PromoterAI

0.052

Neutral

(source)

Varity_R

0.98

gMVP

0.99

Mutation Taster

=5/95

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over