rs104894545

chr17-81510824-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001614.5(ACTG1):c.994C>G(p.Pro332Ala) 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P332P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.49

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 11 ACMG points.

• PM1: In a hotspot region, there are 5 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
• PP2: Missense variant where missense usually causes diseases, ACTG1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 17-81510824-G-C is Pathogenic according to our data. Variant chr17-81510824-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 18317.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-81510824-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG1	NM_001614.5	c.994C>G	p.Pro332Ala	missense_variant	6/6	ENST00000573283.7
ACTG1	NM_001199954.3	c.994C>G	p.Pro332Ala	missense_variant	6/6
ACTG1	NR_037688.3	n.1066C>G		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7	c.994C>G	p.Pro332Ala	missense_variant	6/6	5	NM_001614.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2003

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 23, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACTG1 protein function. This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 332 of the ACTG1 protein (p.Pro332Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with deafness (PMID: 13680526). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18317). Experimental studies have shown that this missense change affects ACTG1 function (PMID: 19419963). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Uncertain	24
Dann	Benign	0.81
DEOGEN2	Pathogenic	0.91	D;D;D;D;D;D
Eigen	Benign	-0.096
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.85	D
Sift4G	Uncertain	0.0080	D;D;D;D;D;.
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.79
MutPred		0.91		Loss of catalytic residue at P332 (P = 0.0271);Loss of catalytic residue at P332 (P = 0.0271);Loss of catalytic residue at P332 (P = 0.0271);Loss of catalytic residue at P332 (P = 0.0271);Loss of catalytic residue at P332 (P = 0.0271);Loss of catalytic residue at P332 (P = 0.0271);
MVP		0.97
ClinPred		0.41	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs104894545; hg19: chr17-79477850;