chr17-50175349-C-T

Position:

• chr17-50175349-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000023.4(SGCA):​c.1076C>T​(p.Thr359Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,082 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

H1-9P (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.1076C>T	p.Thr359Ile	missense_variant	9/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.704C>T	p.Thr235Ile	missense_variant	7/8		NP_001129169.1
SGCA	NR_135553.2	n.903C>T		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.1076C>T	p.Thr359Ile	missense_variant	9/10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246938 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460082 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;D;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.93
MutPred		0.62		.;Loss of glycosylation at T359 (P = 0.0281);.;
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.53
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146924667; hg19: chr17-48252710;