rs281875329

Positions:

• chr17-81511224-G-A
• chr17-81511224-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_001614.5(ACTG1):​c.766C>T​(p.Arg256Trp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4 O:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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, 0.992
• PP5: Variant 17-81511224-G-A is Pathogenic according to our data. Variant chr17-81511224-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 29590.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81511224-G-A is described in Lovd as [Pathogenic]. Variant chr17-81511224-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.766C>T	p.Arg256Trp	missense_variant	4/6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.766C>T	p.Arg256Trp	missense_variant	4/6		NP_001186883.1
ACTG1	NR_037688.3	n.838C>T		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.766C>T	p.Arg256Trp	missense_variant	4/6	5	NM_001614.5	ENSP00000458435	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Alfa AF: 0.0900 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Baraitser-winter syndrome 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 02, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2012	- -

Autosomal dominant nonsyndromic hearing loss 20 Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital

Feb 26, 2019

- -

Lissencephaly Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

not provided Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.93	.;.;D;.;.;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.2	.;D;.;.;.;.
REVEL	Pathogenic	0.86
Sift4G	Uncertain	0.029	D;D;D;D;D;.
Polyphen		0.99	D;D;D;D;D;D
Vest4		0.90
MutPred		0.92		Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);Loss of methylation at R256 (P = 0.108);
MVP		0.99
ClinPred		1.0	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs281875329; hg19: chr17-79478250;