11-66547012-G-C

Variant names:

• chr11-66547012-G-C
• NM_001104.4:c.75G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001104.4(ACTN3):​c.75G>C​(p.Glu25Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• Publications: 0 publications found

Genes affected

ACTN3 (HGNC:165): (actinin alpha 3) This gene encodes a member of the alpha-actin binding protein gene family. The encoded protein is primarily expressed in skeletal muscle and functions as a structural component of sarcomeric Z line. This protein is involved in crosslinking actin containing thin filaments. An allelic polymorphism in this gene results in both coding and non-coding variants; the reference genome represents the coding allele. The non-functional allele of this gene is associated with elite athlete status. [provided by RefSeq, Feb 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1559121).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.75G>C	p.Glu25Asp	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.276+226G>C		intron_variant	Intron 1 of 20		NP_001245300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN3	ENST00000513398.2	c.75G>C	p.Glu25Asp	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000511191.1	n.75G>C		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1
ACTN3	ENST00000502692.5	c.276+226G>C		intron_variant	Intron 1 of 20	2		ENSP00000422007.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1372412 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 674202

African (AFR) AF: 0.00 AC: 0 AN: 30382

American (AMR) AF: 0.00 AC: 0 AN: 29708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20068

East Asian (EAS) AF: 0.00 AC: 0 AN: 38858

South Asian (SAS) AF: 0.00 AC: 0 AN: 70596

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4908

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072370

Other (OTH) AF: 0.00 AC: 0 AN: 56310

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.75G>C (p.E25D) alteration is located in exon 1 (coding exon 1) of the ACTN3 gene. This alteration results from a G to C substitution at nucleotide position 75, causing the glutamic acid (E) at amino acid position 25 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	0.0036	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.16	T
PhyloP100		1.1
Sift4G	Benign	0.71	T
Polyphen		0.0010	B
Vest4		0.15
MVP		0.50
GERP RS		2.3
PromoterAI		0.082	Neutral
Varity_R		0.14

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

hg19: chr11-66314483;