17-81511533-T-C

Position:

• chr17-81511533-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_Moderate

The NM_001614.5(ACTG1):​c.457A>G​(p.Met153Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M153I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.90

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001614.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-81511531-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333817.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP5: Variant 17-81511533-T-C is Pathogenic according to our data. Variant chr17-81511533-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 473006.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG1	NM_001614.5	c.457A>G	p.Met153Val	missense_variant	4/6	ENST00000573283.7
ACTG1	NM_001199954.3	c.457A>G	p.Met153Val	missense_variant	4/6
ACTG1	NR_037688.3	n.529A>G		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7	c.457A>G	p.Met153Val	missense_variant	4/6	5	NM_001614.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2020

This sequence change replaces methionine with valine at codon 153 of the ACTG1 protein (p.Met153Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Baraitser-Winter syndrome (Invitae). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Met153 amino acid residue in ACTG1. Other variant(s) that disrupt this residue have been observed in individuals with ACTG1-related conditions (PMID: 26188271), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	D;D;D;D;D;D;T;T;T;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.0088
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;.;T;.;.;.;T;.;T;T;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-1.1	N;N;N;N;N;N;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.86	.;N;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.50
Sift4G	Benign	0.30	T;T;T;T;T;.;.;.;T;T;T
Polyphen		0.0030	B;B;B;B;B;B;.;.;.;.;.
Vest4		0.83
MutPred		0.29		Loss of disorder (P = 0.1373);Loss of disorder (P = 0.1373);Loss of disorder (P = 0.1373);Loss of disorder (P = 0.1373);Loss of disorder (P = 0.1373);Loss of disorder (P = 0.1373);.;Loss of disorder (P = 0.1373);Loss of disorder (P = 0.1373);Loss of disorder (P = 0.1373);.;
MVP		0.94
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.96

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

LitVar

Other links and lift over

dbSNP: rs1555666789; hg19: chr17-79478559;