NM_001614.5:c.721G>A

Variant names:

• chr17-81511269-C-T
• rs267606631
• NM_001614.5:c.721G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_001614.5(ACTG1):​c.721G>A​(p.Glu241Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001786159: Published functional studies demonstrate a damaging effect as yeast expressing E241K demonstrated impaired growth. E241K also influenced cell morphology and actin cytoskeletal patterns, leading to larger cell size and abnormal randomly distributed thick actin cables and patches as well as an aberrant multi-vacuolar pattern (Morin et al., 2009); SCV000205640: Functional studies performed in yeast suggested that the variant may impact the hair cell's cytoskeletal structure (Morin 2009).; SCV005863198: Experimental studies have shown that this missense change affects ACTG1 function (PMID:19477959).". Synonymous variant affecting the same amino acid position (i.e. E241E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.48
• Publications: 24 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001786159: Published functional studies demonstrate a damaging effect as yeast expressing E241K demonstrated impaired growth. E241K also influenced cell morphology and actin cytoskeletal patterns, leading to larger cell size and abnormal randomly distributed thick actin cables and patches as well as an aberrant multi-vacuolar pattern (Morin et al., 2009); SCV000205640: Functional studies performed in yeast suggested that the variant may impact the hair cell's cytoskeletal structure (Morin 2009).; SCV005863198: Experimental studies have shown that this missense change affects ACTG1 function (PMID: 19477959).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 17-81511269-C-T is Pathogenic according to our data. Variant chr17-81511269-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 18322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.721G>A	p.Glu241Lys	missense	Exon 4 of 6	NP_001605.1	P63261
	ACTG1	NM_001199954.3		c.721G>A	p.Glu241Lys	missense	Exon 4 of 6	NP_001186883.1	P63261
	ACTG1	NR_037688.3		n.793G>A		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTG1	ENST00000573283.7	TSL:5 MANE Select	c.721G>A	p.Glu241Lys	missense	Exon 4 of 6	ENSP00000458435.1	P63261
	ACTG1	ENST00000575842.5	TSL:1	c.721G>A	p.Glu241Lys	missense	Exon 3 of 5	ENSP00000458162.1	P63261
	ACTG1	ENST00000615544.5	TSL:1	c.721G>A	p.Glu241Lys	missense	Exon 4 of 6	ENSP00000477968.1	P63261

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461454 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727050

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal dominant nonsyndromic hearing loss 20 (2)
1	-	-	Autosomal dominant nonsyndromic hearing loss 20;C3281235:Baraitser-winter syndrome 2 (1)
1	-	-	Hearing impairment (1)
1	-	-	not provided (2)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.89
Sift4G	Benign	0.061	T
Polyphen		0.98	D
Vest4		0.92
MutPred		0.94		Gain of methylation at E241 (P = 0.0075)
MVP		0.95
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.98
gMVP		0.96
Mutation Taster		=1/99	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: rs267606631; hg19: chr17-79478295; COSMIC: COSV59510069; COSMIC: COSV59510069;