rs281875325

Positions:

• chr17-81511907-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001614.5(ACTG1):​c.359C>T​(p.Thr120Ile) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.44

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a helix (size 12) in uniprot entity ACTG_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001614.5
• 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, 0.956
• PP5: Variant 17-81511907-G-A is Pathogenic according to our data. Variant chr17-81511907-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81511907-G-A is described in Lovd as [Pathogenic]. Variant chr17-81511907-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.359C>T	p.Thr120Ile	missense_variant	3/6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.359C>T	p.Thr120Ile	missense_variant	3/6		NP_001186883.1
ACTG1	NR_037688.3	n.431C>T		non_coding_transcript_exon_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.359C>T	p.Thr120Ile	missense_variant	3/6	5	NM_001614.5	ENSP00000458435	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Baraitser-winter syndrome 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Feb 28, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 26, 2012	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25052316, 32506774, 27625340, 23756437, 22366783, 35054877) -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 23, 2021

ACMG classification criteria: PS4, PM2, PM6, PP2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;.;D;.;.;.;D;.;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	1.6	L;L;L;L;L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.3	.;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.92
Sift4G	Uncertain	0.045	D;D;D;D;D;.;.;.;D;T
Polyphen		0.21	B;B;B;B;B;B;.;.;.;.
Vest4		0.98
MutPred		0.80		Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);.;Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);Loss of disorder (P = 0.0587);
MVP		0.97
ClinPred		0.99	D
GERP RS		4.5
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)		0.0		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: rs281875325; hg19: chr17-79478933;