rs267606631

Positions:

• chr17-81511269-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001614.5(ACTG1):​c.721G>A​(p.Glu241Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.48

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 15 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). The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 48 curated benign missense variants. GenCC has associacion of the 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 17-81511269-C-T is Pathogenic according to our data. Variant chr17-81511269-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-81511269-C-T is described in Lovd as [Pathogenic]. Variant chr17-81511269-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.721G>A	p.Glu241Lys	missense_variant	4/6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.721G>A	p.Glu241Lys	missense_variant	4/6		NP_001186883.1
ACTG1	NR_037688.3	n.793G>A		non_coding_transcript_exon_variant	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.721G>A	p.Glu241Lys	missense_variant	4/6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461454 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 20 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 15, 2009	- -

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2021	Published functional studies demonstrate a damaging effect as yeast expressing E241K demonstrated impaired growth. E241K also influenced cell morphology and actin cytoskeletal patterns, leading to larger cell size and abnormal randomly distributed thick actin cables and patches as well as an aberrant multi-vacuolar pattern (Morin et al., 2009); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27627659, 19477959, 25792668, 32341388) -

Hearing impairment Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM2_Moderate, PP3_Supporting -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 11, 2016

The p.Glu241Lys variant in ACTG1 has been reported in 3 individuals with hearing loss, segregated in 5 relatives with hearing loss from 2 families (Morin 2009, Miyagawa 2015, LMM unpublished data), and was absent from large population studi es. Functional studies performed in yeast suggested that the variant may impact the hair cell's cytoskeletal structure (Morin 2009). Computational prediction to ols and conservation analyses suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clin ical significance, this variant is likely pathogenic for autosomal dominant hear ing loss. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;D;D;D;D;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	.;.;D;.;.;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	.;D;.;.;.;.;.
REVEL	Pathogenic	0.89
Sift4G	Benign	0.061	T;T;T;T;T;.;.
Polyphen		0.98	D;D;D;D;D;D;.
Vest4		0.92
MutPred		0.94		Gain of methylation at E241 (P = 0.0075);Gain of methylation at E241 (P = 0.0075);Gain of methylation at E241 (P = 0.0075);Gain of methylation at E241 (P = 0.0075);Gain of methylation at E241 (P = 0.0075);Gain of methylation at E241 (P = 0.0075);.;
MVP		0.95
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.98
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: rs267606631; hg19: chr17-79478295; COSMIC: COSV59510069; COSMIC: COSV59510069;