rs104894544

Positions:

• chr17-81511913-T-A
• chr17-81511913-T-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001614.5(ACTG1):​c.353A>T​(p.Lys118Met) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K118N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.58

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 19 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-81511912-C-G is described in Lovd as [Pathogenic].
• 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, 0.989
• PP5: Variant 17-81511913-T-A is Pathogenic according to our data. Variant chr17-81511913-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 18316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81511913-T-A is described in Lovd as [Pathogenic]. Variant chr17-81511913-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.353A>T	p.Lys118Met	missense_variant	3/6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.353A>T	p.Lys118Met	missense_variant	3/6		NP_001186883.1
ACTG1	NR_037688.3	n.425A>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.353A>T	p.Lys118Met	missense_variant	3/6	5	NM_001614.5	ENSP00000458435	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2003

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Aug 18, 2021

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: the c.353A>T, p.(K118M) in ACTG1 gene is absent from population databases (PM2). This variant was identified in a family with autosomal dominant hearing loss and segregated with the eight affected members of it (PMID: 13680526). Besides, the c.353A>T was detected in other family with the same phenotype and it segregated with the six affected relatives (internal data, Laboratory of Physiology and Genetics of Hearing, CONICET Argentina) applying to PP1_Strong and PS4_Supporting rules. In addition to this, a different missense change in the same position which was functional validated (p.K118N; PMID: 19477959) was detected in a family case applying to PM5 criteria. Computational evidence predicted a pathogenic effect of the variant (Revel score: 0,957) meeting PP3 criteria. Considering all the evidence (PM2, PP1_Strong, PS4_Supporting, PM5 and PP3) the c.353A>T is classified as Pathogenic for non-syndromic autosomal dominant hearing loss. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2022

Published functional studies performed in yeast and cultured mammalian cells suggest that this variant may alter actin function (Bryan et al., 2009; Morin et al., 2009; Kruth et al., 2012; Jepsen et al., 2016; Miyajima et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27911912, 26832775, 25792668, 22718764, 13680526, 30599039, 32341388, 27463135, 19477959, 19419963, 34698053, 34997062) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;.;.;.;D;.;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.8	H;H;H;H;H;H;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.3	.;D;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.96
Sift4G	Uncertain	0.025	D;D;D;D;D;.;.;.;D;D
Polyphen		0.40	B;B;B;B;B;B;.;.;.;.
Vest4		0.93
MutPred		0.96		Loss of ubiquitination at K118 (P = 0.0167);Loss of ubiquitination at K118 (P = 0.0167);Loss of ubiquitination at K118 (P = 0.0167);Loss of ubiquitination at K118 (P = 0.0167);Loss of ubiquitination at K118 (P = 0.0167);Loss of ubiquitination at K118 (P = 0.0167);.;Loss of ubiquitination at K118 (P = 0.0167);Loss of ubiquitination at K118 (P = 0.0167);Loss of ubiquitination at K118 (P = 0.0167);
MVP		0.99
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

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: rs104894544; hg19: chr17-79478939;