17-81510431-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001614.5(ACTG1):c.*259C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 598,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ACTG1 NM_001614.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.26

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-81510431-G-A is Benign according to our data. Variant chr17-81510431-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1189483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000263 (40/152308) while in subpopulation NFE AF= 0.000294 (20/68036). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTG1	NM_001614.5	c.*259C>T		3_prime_UTR_variant	6/6	ENST00000573283.7
ACTG1	NM_001199954.3	c.*259C>T		3_prime_UTR_variant	6/6
ACTG1	NR_037688.3	n.1411+48C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTG1	ENST00000573283.7	c.*259C>T		3_prime_UTR_variant	6/6	5	NM_001614.5	P4

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000401 AC: 49 AN: 122056 Hom.: 0 AF XY: 0.000412 AC XY: 27 AN XY: 65534

Gnomad AFR exome AF: 0.000471

Gnomad AMR exome AF: 0.000523

Gnomad ASJ exome AF: 0.000910

Gnomad EAS exome AF: 0.0000951

Gnomad SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.000428

Gnomad OTH exome AF: 0.000807

GnomAD4 exome AF: 0.000309 AC: 138 AN: 446294 Hom.: 0 Cov.: 5 AF XY: 0.000282 AC XY: 68 AN XY: 241160

Gnomad4 AFR exome AF: 0.000532

Gnomad4 AMR exome AF: 0.000502

Gnomad4 ASJ exome AF: 0.000511

Gnomad4 EAS exome AF: 0.0000864

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000431

Gnomad4 NFE exome AF: 0.000314

Gnomad4 OTH exome AF: 0.000582

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74466

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000355

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	8.5
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs540974291; hg19: chr17-79477457;