rs35130237

chr17-50168409-C-Achr17-50168409-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000023.4(SGCA):c.421C>A(p.Arg141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,589,732 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (4 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:4
• Conservation: PhyloP100: 0.159

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000023.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.016697764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCA	NM_000023.4	c.421C>A	p.Arg141Ser	missense_variant	5/10	ENST00000262018.8
SGCA	NM_001135697.3	c.421C>A	p.Arg141Ser	missense_variant	5/8
SGCA	NR_135553.2	n.457C>A		non_coding_transcript_exon_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCA	ENST00000262018.8	c.421C>A	p.Arg141Ser	missense_variant	5/10	1	NM_000023.4	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000596 AC: 125 AN: 209650 Hom.: 0 AF XY: 0.000559 AC XY: 63 AN XY: 112668

Gnomad AFR exome AF: 0.0000792

Gnomad AMR exome AF: 0.000992

Gnomad ASJ exome AF: 0.000217

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000191

Gnomad FIN exome AF: 0.0000562

Gnomad NFE exome AF: 0.000857

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000837 AC: 1203 AN: 1437470 Hom.: 4 Cov.: 33 AF XY: 0.000810 AC XY: 577 AN XY: 712550

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.00115

Gnomad4 ASJ exome AF: 0.000351

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.000973

Gnomad4 OTH exome AF: 0.000606

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74444

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000765

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000792 Hom.: 0

Bravo AF: 0.000888

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000455 AC: 55

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 30, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 28, 2020	The SGCA c.421C>A; p.Arg141Ser variant (rs35130237) is reported in the literature in several individuals affected with limb-girdle muscular dystrophy or a related sarcoglycanopathy, although a second SGCA variant was not detected in affected individuals (Boito 2003, Trabelsi 2008). The p.Arg141Ser variant is found in the Latino population with an allele frequency of 0.11% (33/31084 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 197618). The arginine at codon 141 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, computational analyses of splicing (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site, although RNA analyses would be required to confirm this. Given the lack of clinical and functional data, the significance of the p.Arg141Ser variant is uncertain at this time. References: Boito C et al. Novel sarcoglycan gene mutations in a large cohort of Italian patients. J Med Genet. 2003 May;40(5):e67. Trabelsi M et al. Revised spectrum of mutations in sarcoglycanopathies. Eur J Hum Genet. 2008 Jul;16(7):793-803. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 29, 2019	- -

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 21, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2021	Observed in a patient in the published literature (Boito et al., 2003) with limb-girdle muscular dystrophy who did not have another pathogenic SGCA variant; however, this patient had only mild reduction in alpha-sarcoglycan and normal beta-, delta-, and gamma-sarcoglycan proteins on immunoblot screning on muscle biopsy and Western blot of muscle protein showed a 40% reduction in alpha-sarcoglycan protein; In silico analysis supports that this missense variant does not alter protein structure/function; However, in silico analysis supports this missense variant has a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 18285821, 12746421, 24742800, 31931849) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 17, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Dec 06, 2017

- -

Sarcoglycanopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 24, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Uncertain	0.29	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.64	N;N;N
REVEL	Uncertain	0.60
Sift	Benign	0.12	T;T;D
Sift4G	Uncertain	0.057	T;T;D
Polyphen		0.96	D;B;.
Vest4		0.56
MVP		0.94
MPC		0.39
ClinPred		0.016	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs35130237; hg19: chr17-48245770;