17-50167487-G-T

Variant names:

• chr17-50167487-G-T
• NM_000023.4:c.157G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000023.4(SGCA):​c.157G>T​(p.Ala53Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCA NM_000023.4 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.71

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_pathogenic. Variant got 7 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 chr17-50167487-G-A is described in Lovd as [Pathogenic].
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4	c.157G>T	p.Ala53Ser	missense_variant, splice_region_variant	Exon 2 of 10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.157G>T	p.Ala53Ser	missense_variant, splice_region_variant	Exon 2 of 8		NP_001129169.1
SGCA	NR_135553.2	n.193G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.157G>T	p.Ala53Ser	missense_variant, splice_region_variant	Exon 2 of 10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:1

Sep 19, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Uncertain	0.62	.;D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Uncertain	-0.022	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.68	N;N
REVEL	Benign	0.26
Sift	Benign	0.94	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.24	B;B
Vest4		0.15
MutPred		0.57		Gain of glycosylation at A53 (P = 0.0135);Gain of glycosylation at A53 (P = 0.0135);
MVP		0.88
MPC		0.32
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.046
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.65		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.65		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-48244848;