17-81512098-G-C

Variant names:

• chr17-81512098-G-C
• rs368299537
• NM_001614.5:c.168C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001614.5(ACTG1):​c.168C>G​(p.Asp56Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.197

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACTG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 48 curated benign missense variants. Gene score misZ: 3.16 (above the threshold of 3.09). Trascript score misZ: 4.8823 (above the threshold of 3.09). GenCC associations: The gene is linked to Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss, Baraitser-Winter cerebrofrontofacial syndrome, autosomal dominant nonsyndromic hearing loss 20.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.168C>G	p.Asp56Glu	missense_variant	Exon 3 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.168C>G	p.Asp56Glu	missense_variant	Exon 3 of 6		NP_001186883.1
ACTG1	NR_037688.3	n.240C>G		non_coding_transcript_exon_variant	Exon 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.168C>G	p.Asp56Glu	missense_variant	Exon 3 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250878 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	.;.;D;.;.;.;T;.;T;T;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.9	L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	.;N;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.60
Sift4G	Benign	0.14	T;T;T;T;T;.;.;.;T;T;T
Polyphen		0.0	B;B;B;B;B;B;.;.;.;.;.
Vest4		0.81
MutPred		0.73		Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);.;Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);Gain of ubiquitination at K61 (P = 0.0931);
MVP		0.96
ClinPred		0.083	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368299537; hg19: chr17-79479124;