ENST00000435422.7:c.-369A>T

Variant names:

• chr5-156326864-A-T
• rs7724969
• ENST00000435422.7:c.-369A>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000435422.7(SGCD):​c.-369A>T variant causes a 5 prime UTR premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.299
• Publications: 5 publications found

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]

SGCD Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2F

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1L

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

LOC124901120 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SGCD	XM_017009724.2	c.-43-2670A>T		intron_variant	Intron 2 of 9		XP_016865213.1
SGCD	XM_047417518.1	c.-43-2670A>T		intron_variant	Intron 4 of 11		XP_047273474.1
SGCD	XM_047417519.1	c.-43-2670A>T		intron_variant	Intron 3 of 10		XP_047273475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCD	ENST00000435422.7	c.-369A>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1		ENSP00000403003.2
SGCD	ENST00000435422.7	c.-369A>T		5_prime_UTR_variant	Exon 1 of 8	1		ENSP00000403003.2
SGCD	ENST00000517913.5	c.-43-2670A>T		intron_variant	Intron 3 of 9	5		ENSP00000429378.1
SGCD	ENST00000524347.2	n.-412A>T		upstream_gene_variant		5		ENSP00000430794.1

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

African (AFR) AF: 0.333 AC: 4 AN: 12

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.333 AC: 2 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.156 AC: 20 AN: 128

Other (OTH) AF: 0.125 AC: 1 AN: 8

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

African (AFR) AF: 0.189 AC: 7869 AN: 41542

American (AMR) AF: 0.177 AC: 2715 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 621 AN: 3468

East Asian (EAS) AF: 0.0478 AC: 248 AN: 5186

South Asian (SAS) AF: 0.272 AC: 1312 AN: 4830

European-Finnish (FIN) AF: 0.221 AC: 2346 AN: 10600

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13059 AN: 67990

Other (OTH) AF: 0.192 AC: 405 AN: 2114

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 27, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.6
DANN	Benign	0.57
PhyloP100		0.30
PromoterAI		-0.067	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7724969; hg19: chr5-155753874;