SGCA p.Ile103Asn

Variant names:

• chr17-50167732-T-A
• rs1161291343
• NM_000023.4:c.308T>A
• SGCA p.Ile103Asn

Your query was ambiguous. Multiple possible variants found:

• chr17-50167732-T-A
• chr17-50167732-TT-AC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_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. I103V) has been classified as Uncertain significance. The gene SGCA is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCA NM_000023.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.86
• Publications: 3 publications found

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]

SGCA Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2D

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Myriad Women's Health, Labcorp Genetics (formerly Invitae)

ENSG00000253730 (HGNC:):

ACMG classification

Specifications for SGCA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain 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 chr17-50167732-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000023.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	NM_000023.4	MANE Select	c.308T>A	p.Ile103Asn	missense	Exon 3 of 10	NP_000014.1	A0A0S2Z4Q1
	SGCA	NM_001135697.3		c.308T>A	p.Ile103Asn	missense	Exon 3 of 8	NP_001129169.1	A0A0S2Z4P8
	SGCA	NR_135553.2		n.344T>A		non_coding_transcript_exon	Exon 3 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCA	ENST00000262018.8	TSL:1 MANE Select	c.308T>A	p.Ile103Asn	missense	Exon 3 of 10	ENSP00000262018.3	Q16586-1
	SGCA	ENST00000344627.10	TSL:1	c.308T>A	p.Ile103Asn	missense	Exon 3 of 8	ENSP00000345522.6	Q16586-2
	SGCA	ENST00000952408.1		c.398T>A	p.Ile133Asn	missense	Exon 3 of 10	ENSP00000622467.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1161291343;

hg19: chr17-48245093;