rs146924667
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000023.4(SGCA):c.1076C>A(p.Thr359Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000067 in 1,612,356 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000063 ( 1 hom. )
Consequence
SGCA
NM_000023.4 missense
NM_000023.4 missense
Scores
6
9
2
Clinical Significance
Conservation
PhyloP100: 7.08
Genes affected
SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCA | NM_000023.4 | c.1076C>A | p.Thr359Asn | missense_variant | 9/10 | ENST00000262018.8 | |
SGCA | NM_001135697.3 | c.704C>A | p.Thr235Asn | missense_variant | 7/8 | ||
SGCA | NR_135553.2 | n.903C>A | non_coding_transcript_exon_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCA | ENST00000262018.8 | c.1076C>A | p.Thr359Asn | missense_variant | 9/10 | 1 | NM_000023.4 | P1 | |
ENST00000504307.3 | n.547-3172G>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152274Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000688 AC: 17AN: 246938Hom.: 0 AF XY: 0.0000893 AC XY: 12AN XY: 134330
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GnomAD4 exome AF: 0.0000630 AC: 92AN: 1460082Hom.: 1 Cov.: 31 AF XY: 0.0000633 AC XY: 46AN XY: 726320
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GnomAD4 genome ? AF: 0.000105 AC: 16AN: 152274Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74394
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 359 of the SGCA protein (p.Thr359Asn). This variant is present in population databases (rs146924667, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SGCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 500012). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGCA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 20, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 24, 2020 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 02, 2024 | The c.1076C>A (p.T359N) alteration is located in exon 9 (coding exon 9) of the SGCA gene. This alteration results from a C to A substitution at nucleotide position 1076, causing the threonine (T) at amino acid position 359 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 20, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;T
Polyphen
D;D;.
Vest4
MVP
MPC
1.2
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 27
Find out detailed SpliceAI scores and Pangolin per-transcript scores at