rs281875330

Variant names:

• chr17-81511626-T-C
• rs281875330
• NM_001614.5:c.364A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_001614.5(ACTG1):​c.364A>G​(p.Ile122Val) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as not provided (no stars). Synonymous variant affecting the same amino acid position (i.e. I122I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG1 NM_001614.5 missense, splice_region
• Scores: Splicing: ADA: 0.00008245
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.58
• Publications: 12 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001614.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.364A>G	p.Ile122Val	missense_variant, splice_region_variant	Exon 4 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.364A>G	p.Ile122Val	missense_variant, splice_region_variant	Exon 4 of 6		NP_001186883.1
ACTG1	NR_037688.3	n.436A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTG1	ENST00000573283.7	c.364A>G	p.Ile122Val	missense_variant, splice_region_variant	Exon 4 of 6	5	NM_001614.5	ENSP00000458435.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Benign	0.88
DEOGEN2	Uncertain	0.67	D;D;D;D;D;D;T;T;T;T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.046
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;.;D;.;.;.;D;.;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.6	L;L;L;L;L;L;.;.;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.77	.;N;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.68
Sift4G	Benign	0.063	T;T;T;T;T;.;.;.;T;T
Polyphen		0.0010	B;B;B;B;B;B;.;.;.;.
Vest4		0.65
MutPred		0.88		Loss of methylation at K118 (P = 0.0994);Loss of methylation at K118 (P = 0.0994);Loss of methylation at K118 (P = 0.0994);Loss of methylation at K118 (P = 0.0994);Loss of methylation at K118 (P = 0.0994);Loss of methylation at K118 (P = 0.0994);.;Loss of methylation at K118 (P = 0.0994);Loss of methylation at K118 (P = 0.0994);Loss of methylation at K118 (P = 0.0994);
MVP		0.81
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.80
gMVP		0.90
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000082
dbscSNV1_RF	Benign	0.0
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: rs281875330; hg19: chr17-79478652;