17-81512304-G-C

Position:

• chr17-81512304-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001614.5(ACTG1):​c.51C>G​(p.Cys17Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23

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 Uncertain_significance. Variant got 5 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). 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, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.51C>G	p.Cys17Trp	missense_variant	2/6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.51C>G	p.Cys17Trp	missense_variant	2/6		NP_001186883.1
ACTG1	NR_037688.3	n.123C>G		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.51C>G	p.Cys17Trp	missense_variant	2/6	5	NM_001614.5	ENSP00000458435	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74462

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;D;.;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.7	.;D;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.78
Sift4G	Pathogenic	0.0	D;D;D;D;D;.;.;.;D;D;D
Polyphen		1.0	D;D;D;D;D;D;.;.;.;.;.
Vest4		0.92
MutPred		0.33		Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);Loss of methylation at K18 (P = 0.0768);
MVP		0.99
ClinPred		1.0	D
GERP RS		2.9
Varity_R		0.98
gMVP		0.99

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-79479330; COSMIC: COSV59512020; COSMIC: COSV59512020;