8-14090634-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_139167.4(SGCZ):c.748T>C(p.Phe250Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,456,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SGCZ NM_139167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

Genes affected

SGCZ (HGNC:14075): (sarcoglycan zeta) The zeta-sarcoglycan gene measures over 465 kb and localizes to 8p22. This protein is part of the sarcoglycan complex, a group of 6 proteins. The sarcoglycans are all N-glycosylated transmembrane proteins with a short intra-cellular domain, a single transmembrane region and a large extra-cellular domain containing a carboxyl-terminal cluster with several conserved cysteine residues. The sarcoglycan complex is part of the dystrophin-associated glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extra-cellular matrix. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3313733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCZ	NM_139167.4	c.748T>C	p.Phe250Leu	missense_variant	8/8	ENST00000382080.6
SGCZ	NM_001322879.2	c.646T>C	p.Phe216Leu	missense_variant	7/7
SGCZ	NM_001322880.2	c.625T>C	p.Phe209Leu	missense_variant	7/7
SGCZ	NM_001322881.2	c.403T>C	p.Phe135Leu	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCZ	ENST00000382080.6	c.748T>C	p.Phe250Leu	missense_variant	8/8	5	NM_139167.4	P1
SGCZ	ENST00000421524.6	c.607T>C	p.Phe203Leu	missense_variant	6/6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1456602 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 724694

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000469 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2022

The c.748T>C (p.F250L) alteration is located in exon 8 (coding exon 8) of the SGCZ gene. This alteration results from a T to C substitution at nucleotide position 748, causing the phenylalanine (F) at amino acid position 250 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	20
Dann	Benign	0.91
Eigen	Benign	-0.12
Eigen_PC	Benign	0.072
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.79	N;N
REVEL	Uncertain	0.29
Sift	Benign	0.67	T;T
Sift4G	Benign	0.68	T;T
Polyphen		0.0040	B;B
Vest4		0.27
MutPred		0.28		.;Loss of catalytic residue at F203 (P = 0.0731);
MVP		0.78
MPC		0.0092
ClinPred		0.72	D
GERP RS		5.4
gMVP		0.41

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

Other links and lift over

dbSNP: rs1801661800; hg19: chr8-13948143;