NM_001614.5:c.833C>T

Variant names:

• chr17-81511078-G-A
• rs28999112
• NM_001614.5:c.833C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS3 PM1 PM2 PP3_Moderate PP5

The NM_001614.5(ACTG1):​c.833C>T​(p.Thr278Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002243715: Experimental studies have shown that this missense change affects ACTG1 function (PMID:19419963).". Synonymous variant affecting the same amino acid position (i.e. T278T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 9.49
• Publications: 20 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, G2P, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

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

  Inheritance: AD Classification: STRONG Submitted by: 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: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002243715: Experimental studies have shown that this missense change affects ACTG1 function (PMID: 19419963).
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001614.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 17-81511078-G-A is Pathogenic according to our data. Variant chr17-81511078-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18319.

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.833C>T	p.Thr278Ile	missense	Exon 5 of 6	NP_001605.1	P63261
	ACTG1	NM_001199954.3		c.833C>T	p.Thr278Ile	missense	Exon 5 of 6	NP_001186883.1	P63261
	ACTG1	NR_037688.3		n.905C>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.833C>T	p.Thr278Ile	missense	Exon 5 of 6	ENSP00000458435.1	P63261
	ACTG1	ENST00000575842.5	TSL:1	c.833C>T	p.Thr278Ile	missense	Exon 4 of 5	ENSP00000458162.1	P63261
	ACTG1	ENST00000615544.5	TSL:1	c.833C>T	p.Thr278Ile	missense	Exon 5 of 6	ENSP00000477968.1	P63261

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	0.064
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	0.66	N
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.85
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.95
MutPred		0.74		Loss of glycosylation at T278 (P = 0.131)
MVP		0.96
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs28999112; hg19: chr17-79478104;