11-66547043-G-T

Variant names:

• chr11-66547043-G-T
• rs201937354
• NM_001104.4:c.106G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001104.4(ACTN3):​c.106G>T​(p.Asp36Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000735 in 1,359,630 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D36H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.89
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.106G>T	p.Asp36Tyr	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.276+257G>T		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.106G>T	p.Asp36Tyr	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000511191.1	n.106G>T		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1
ACTN3	ENST00000502692.5	c.276+257G>T		intron_variant	Intron 1 of 20	2		ENSP00000422007.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1359630 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 665290

African (AFR) AF: 0.00 AC: 0 AN: 30048

American (AMR) AF: 0.00 AC: 0 AN: 28534

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19754

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38478

South Asian (SAS) AF: 0.00 AC: 0 AN: 69674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4330

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063808

Other (OTH) AF: 0.00 AC: 0 AN: 55688

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.87	D
PhyloP100		5.9
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.78
MVP		0.77
GERP RS		3.3
PromoterAI		-0.12	Neutral
Varity_R		0.26

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: rs201937354; hg19: chr11-66314514;