5-156326864-A-T

Position:

• chr5-156326864-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000435422.7(SGCD):​c.-369A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,414 control chromosomes in the GnomAD database, including 2,853 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (2850 hom., cov: 33)
  • Exomes 𝑓: 0.16 (3 hom.)
• Consequence: SGCD ENST00000435422.7 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.299

Genes affected

SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

LOC124901120 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-156326864-A-T is Benign according to our data. Variant chr5-156326864-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48113.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC124901120	XR_007059016.1	n.234+20589T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCD	ENST00000435422.7	c.-369A>T		5_prime_UTR_variant	1/8	1		A1
SGCD	ENST00000517913.5	c.-43-2670A>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28925 AN: 152126 Hom.: 2851 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.194

GnomAD4 exome AF: 0.165 AC: 28 AN: 170 Hom.: 3 Cov.: 0 AF XY: 0.174 AC XY: 23 AN XY: 132

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.190 AC: 28941 AN: 152244 Hom.: 2850 Cov.: 33 AF XY: 0.191 AC XY: 14212 AN XY: 74442

Gnomad4 AFR AF: 0.189

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.0478

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.221

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.192

Alfa AF: 0.100 Hom.: 164

Bravo AF: 0.185

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Qualitative or quantitative defects of delta-sarcoglycan Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 27, 2011

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.6
DANN	Benign	0.57

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: rs7724969; hg19: chr5-155753874;