Variant chr17-81512060-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_001614.5(ACTG1):c.206A>T(p.Tyr69Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,664 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.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ACTG1
NM_001614.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.58

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ACTG1	NM_001614.5 linkuse as main transcript	c.206A>T	p.Tyr69Phe	missense_variant	3/6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3 linkuse as main transcript	c.206A>T	p.Tyr69Phe	missense_variant	3/6		NP_001186883.1
ACTG1	NR_037688.3 linkuse as main transcript	n.278A>T		non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7 linkuse as main transcript	c.206A>T	p.Tyr69Phe	missense_variant	3/6	5	NM_001614.5	ENSP00000458435	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251132

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.89

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.97

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.4

.;N;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.86

Sift4G

Uncertain

0.0080

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

Polyphen

0.97

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

Vest4

0.68

MutPred

0.85

Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);.;Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);Gain of catalytic residue at Y69 (P = 0.0745);

MVP

0.96

ClinPred

0.91

GERP RS

4.0

Varity_R

0.97

gMVP

0.91

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over