chr11-66547043-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001104.4(ACTN3):​c.106G>C​(p.Asp36His) variant causes a missense change. The variant allele was found at a frequency of 0.000668 in 1,511,952 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00071 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (8 hom.)
• Consequence: ACTN3 NM_001104.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.89
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027109325).
• BP6: Variant 11-66547043-G-C is Benign according to our data. Variant chr11-66547043-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3033952.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN3	NM_001104.4	c.106G>C	p.Asp36His	missense_variant	Exon 1 of 21	ENST00000513398.2	NP_001095.2
ACTN3	NM_001258371.3	c.276+257G>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.106G>C	p.Asp36His	missense_variant	Exon 1 of 21	1	NM_001104.4	ENSP00000426797.1
ACTN3	ENST00000511191.1	n.106G>C		non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000426236.1
ACTN3	ENST00000502692.5	c.276+257G>C		intron_variant	Intron 1 of 20	2		ENSP00000422007.1

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00656

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00119 AC: 199 AN: 167724 AF XY: 0.00116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00565

Gnomad FIN exome AF: 0.00488

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00238

GnomAD4 exome AF: 0.000663 AC: 902 AN: 1359628 Hom.: 8 Cov.: 32 AF XY: 0.000643 AC XY: 428 AN XY: 665288

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: 0.0122 AC: 468 AN: 38476

South Asian (SAS) AF: 0.000273 AC: 19 AN: 69674

European-Finnish (FIN) AF: 0.00458 AC: 226 AN: 49316

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

European-Non Finnish (NFE) AF: 0.000135 AC: 144 AN: 1063808

Other (OTH) AF: 0.000808 AC: 45 AN: 55688

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

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

East Asian (EAS) AF: 0.00638 AC: 33 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000975 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00106 AC: 126

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ACTN3-related disorder Benign:1

Jul 10, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.027	T
PhyloP100		5.9
Sift4G	Uncertain	0.0090	D
Polyphen		0.98	D
Vest4		0.76
MVP		0.68
GERP RS		3.3
PromoterAI		-0.053	Neutral
Varity_R		0.25

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;