rs1135989

Variant names:

• chr17-81510981-G-A
• rs1135989
• NM_001614.5:c.930C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-81510981-G-A
• chr17-81510981-G-C
• chr17-81510981-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001614.5(ACTG1):​c.930C>T​(p.Ala310Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,808 control chromosomes in the GnomAD database, including 104,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A310A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7714 hom., cov: 33)
  • Exomes 𝑓: 0.35 (96769 hom.)
• Consequence: ACTG1 NM_001614.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.40
• Publications: 34 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-81510981-G-A is Benign according to our data. Variant chr17-81510981-G-A is described in ClinVar as Benign. ClinVar VariationId is 44151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.39 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001614.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTG1	NM_001614.5	MANE Select	c.930C>T	p.Ala310Ala	synonymous	Exon 5 of 6	NP_001605.1
	ACTG1	NM_001199954.3		c.930C>T	p.Ala310Ala	synonymous	Exon 5 of 6	NP_001186883.1
	ACTG1	NR_037688.3		n.1002C>T		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTG1	ENST00000573283.7	TSL:5 MANE Select	c.930C>T	p.Ala310Ala	synonymous	Exon 5 of 6	ENSP00000458435.1
	ACTG1	ENST00000575842.5	TSL:1	c.930C>T	p.Ala310Ala	synonymous	Exon 4 of 5	ENSP00000458162.1
	ACTG1	ENST00000615544.5	TSL:1	c.930C>T	p.Ala310Ala	synonymous	Exon 5 of 6	ENSP00000477968.1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45656 AN: 151958 Hom.: 7716 Cov.: 33

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.229

Gnomad NFE AF: 0.391

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.287 AC: 72134 AN: 251338 AF XY: 0.290

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.183

Gnomad ASJ exome AF: 0.335

Gnomad EAS exome AF: 0.00163

Gnomad FIN exome AF: 0.416

Gnomad NFE exome AF: 0.380

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.350 AC: 512264 AN: 1461732 Hom.: 96769 Cov.: 90 AF XY: 0.346 AC XY: 251336 AN XY: 727186

African (AFR) AF: 0.180 AC: 6035 AN: 33472

American (AMR) AF: 0.191 AC: 8563 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8946 AN: 26136

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39700

South Asian (SAS) AF: 0.177 AC: 15231 AN: 86256

European-Finnish (FIN) AF: 0.412 AC: 21953 AN: 53332

Middle Eastern (MID) AF: 0.225 AC: 1298 AN: 5760

European-Non Finnish (NFE) AF: 0.387 AC: 430585 AN: 1111962

Other (OTH) AF: 0.325 AC: 19607 AN: 60392

GnomAD4 genome AF: 0.300 AC: 45636 AN: 152076 Hom.: 7714 Cov.: 33 AF XY: 0.297 AC XY: 22063 AN XY: 74340

African (AFR) AF: 0.188 AC: 7800 AN: 41498

American (AMR) AF: 0.259 AC: 3961 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1193 AN: 3470

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5182

South Asian (SAS) AF: 0.163 AC: 786 AN: 4816

European-Finnish (FIN) AF: 0.415 AC: 4383 AN: 10564

Middle Eastern (MID) AF: 0.219 AC: 64 AN: 292

European-Non Finnish (NFE) AF: 0.391 AC: 26585 AN: 67968

Other (OTH) AF: 0.305 AC: 642 AN: 2106

Alfa AF: 0.328 Hom.: 3709

Bravo AF: 0.281

Asia WGS AF: 0.0760 AC: 265 AN: 3478

EpiCase AF: 0.381

EpiControl AF: 0.377

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Autosomal dominant nonsyndromic hearing loss 20 (1)
-	-	1	Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 (1)
-	-	1	Baraitser-winter syndrome 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.4
DANN	Benign	0.93
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs1135989; hg19: chr17-79478007; COSMIC: COSV59510220; COSMIC: COSV59510220;