rs1161291343

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000023.4(SGCA):​c.308T>A​(p.Ile103Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. I103F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SGCA
NM_000023.4 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.86
Variant links:
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a topological_domain Extracellular (size 266) in uniprot entity SGCA_HUMAN there are 108 pathogenic changes around while only 2 benign (98%) in NM_000023.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-50167731-A-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SGCANM_000023.4 linkuse as main transcriptc.308T>A p.Ile103Asn missense_variant 3/10 ENST00000262018.8 NP_000014.1 Q16586-1A0A0S2Z4Q1
SGCANM_001135697.3 linkuse as main transcriptc.308T>A p.Ile103Asn missense_variant 3/8 NP_001129169.1 Q16586-2A0A0S2Z4P8
SGCANR_135553.2 linkuse as main transcriptn.344T>A non_coding_transcript_exon_variant 3/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SGCAENST00000262018.8 linkuse as main transcriptc.308T>A p.Ile103Asn missense_variant 3/101 NM_000023.4 ENSP00000262018.3 Q16586-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
.;D
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.5
M;M
PrimateAI
Uncertain
0.53
T
PROVEAN
Pathogenic
-4.4
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;D
Vest4
0.93
MutPred
0.92
Gain of disorder (P = 0.0316);Gain of disorder (P = 0.0316);
MVP
1.0
MPC
1.5
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.85
gMVP
0.99

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1161291343; hg19: chr17-48245093; API