rs11549196

Variant names:

• chr17-81511560-C-A
• rs11549196
• NM_001614.5:c.430G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-81511560-C-A
• chr17-81511560-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Strong

The NM_001614.5(ACTG1):​c.430G>T​(p.Ala144Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A144P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTG1 NM_001614.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-81511560-C-G is described in Lovd as [Likely_pathogenic].
• PP2: Missense variant in the ACTG1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 49 curated pathogenic missense variants (we use a threshold of 10). The gene has 48 curated benign missense variants. Gene score misZ: 3.16 (above the threshold of 3.09). Trascript score misZ: 4.8823 (above the threshold of 3.09). GenCC associations: The gene is linked to Baraitser-winter syndrome 2, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss, Baraitser-Winter cerebrofrontofacial syndrome, autosomal dominant nonsyndromic hearing loss 20.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTG1	NM_001614.5	c.430G>T	p.Ala144Ser	missense_variant	Exon 4 of 6	ENST00000573283.7	NP_001605.1
ACTG1	NM_001199954.3	c.430G>T	p.Ala144Ser	missense_variant	Exon 4 of 6		NP_001186883.1
ACTG1	NR_037688.3	n.502G>T		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.430G>T	p.Ala144Ser	missense_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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Benign	0.92
DEOGEN2	Uncertain	0.78	D;D;D;D;D;D;T;T;T;T;.
Eigen	Benign	-0.049
Eigen_PC	Benign	0.057
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;D;.;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.84	L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	.;N;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.76
Sift4G	Benign	0.21	T;T;T;T;T;.;.;.;T;T;T
Polyphen		0.0020	B;B;B;B;B;B;.;.;.;.;.
Vest4		0.70
MutPred		0.90		Gain of disorder (P = 0.0347);Gain of disorder (P = 0.0347);Gain of disorder (P = 0.0347);Gain of disorder (P = 0.0347);Gain of disorder (P = 0.0347);Gain of disorder (P = 0.0347);.;Gain of disorder (P = 0.0347);Gain of disorder (P = 0.0347);Gain of disorder (P = 0.0347);.;
MVP		0.96
ClinPred		0.87	D
GERP RS		4.6
Varity_R		0.91
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs11549196; hg19: chr17-79478586;