11-66546978-A-C

Variant names:

• chr11-66546978-A-C
• rs767048407
• NM_001104.4:c.41A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001104.4(ACTN3):​c.41A>C​(p.Glu14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000302 in 1,522,658 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E14K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000088 (0 hom.)
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.614
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.095356464).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.41A>C	p.Glu14Ala	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.276+192A>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.41A>C	p.Glu14Ala	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000511191.1	n.41A>C		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1
ACTN3	ENST00000502692.5	c.276+192A>C		intron_variant	Intron 1 of 20	2		ENSP00000422007.1

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151784 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00 AC: 0 AN: 157714 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000875 AC: 12 AN: 1370874 Hom.: 0 Cov.: 32 AF XY: 0.00000446 AC XY: 3 AN XY: 673230

African (AFR) AF: 0.00 AC: 0 AN: 30402

American (AMR) AF: 0.000272 AC: 8 AN: 29434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20342

East Asian (EAS) AF: 0.00 AC: 0 AN: 38558

South Asian (SAS) AF: 0.00 AC: 0 AN: 70776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5250

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071090

Other (OTH) AF: 0.0000710 AC: 4 AN: 56314

GnomAD4 genome AF: 0.000224 AC: 34 AN: 151784 Hom.: 0 Cov.: 32 AF XY: 0.000189 AC XY: 14 AN XY: 74142

African (AFR) AF: 0.00 AC: 0 AN: 41258

American (AMR) AF: 0.00203 AC: 31 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67932

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000525

ExAC AF: 0.00000836 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41A>C (p.E14A) alteration is located in exon 1 (coding exon 1) of the ACTN3 gene. This alteration results from a A to C substitution at nucleotide position 41, causing the glutamic acid (E) at amino acid position 14 to be replaced by an alanine (A). 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	0.086
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.095	T
PhyloP100		0.61
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.29
MVP		0.53
GERP RS		0.45
PromoterAI		-0.030	Neutral
Varity_R		0.049

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: rs767048407; hg19: chr11-66314449;