ENST00000574671.6:n.1720G>C

Variant names:

• chr17-81510498-C-G
• rs3204704
• ENST00000574671.6:n.1720G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000574671.6(ACTG1):​n.1720G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 779,208 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (223 hom., cov: 32)
  • Exomes 𝑓: 0.018 (203 hom.)
• Consequence: ACTG1 ENST00000574671.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.80
• Publications: 2 publications found

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]

ACTG1 Gene-Disease associations (from GenCC):

• Baraitser-winter syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss 20

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Baraitser-Winter cerebrofrontofacial syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 17-81510498-C-G is Benign according to our data. Variant chr17-81510498-C-G is described in ClinVar as [Benign]. Clinvar id is 1268147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.*192G>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NR_037688.3	n.1392G>C		non_coding_transcript_exon_variant	Exon 6 of 7
ACTG1	NM_001199954.3	c.*192G>C		3_prime_UTR_variant	Exon 6 of 6		NP_001186883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.*192G>C		3_prime_UTR_variant	Exon 6 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes AF: 0.0403 AC: 6126 AN: 152170 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0300

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0412

GnomAD2 exomes AF: 0.0223 AC: 3248 AN: 145614 AF XY: 0.0209

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0479

Gnomad EAS exome AF: 0.0297

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0137

Gnomad OTH exome AF: 0.0208

GnomAD4 exome AF: 0.0175 AC: 10975 AN: 626920 Hom.: 203 Cov.: 8 AF XY: 0.0169 AC XY: 5665 AN XY: 334630

African (AFR) AF: 0.0936 AC: 1582 AN: 16906

American (AMR) AF: 0.0206 AC: 715 AN: 34634

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 1000 AN: 20362

East Asian (EAS) AF: 0.0206 AC: 664 AN: 32228

South Asian (SAS) AF: 0.0166 AC: 1059 AN: 63958

European-Finnish (FIN) AF: 0.00534 AC: 207 AN: 38752

Middle Eastern (MID) AF: 0.0197 AC: 51 AN: 2594

European-Non Finnish (NFE) AF: 0.0127 AC: 4869 AN: 384728

Other (OTH) AF: 0.0253 AC: 828 AN: 32758

GnomAD4 genome AF: 0.0403 AC: 6135 AN: 152288 Hom.: 223 Cov.: 32 AF XY: 0.0399 AC XY: 2970 AN XY: 74476

African (AFR) AF: 0.101 AC: 4176 AN: 41550

American (AMR) AF: 0.0300 AC: 459 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3472

East Asian (EAS) AF: 0.0329 AC: 171 AN: 5190

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4828

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 918 AN: 68022

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0280 Hom.: 20

Bravo AF: 0.0439

Asia WGS AF: 0.0400 AC: 137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3204704; hg19: chr17-79477524;