13-47943043-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003850.3(SUCLA2):c.*328A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 302,492 control chromosomes in the GnomAD database, including 2,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.085 (728 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1311 hom.)
• Consequence: SUCLA2 NM_003850.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.766

Genes affected

SUCLA2 (HGNC:11448): (succinate-CoA ligase ADP-forming subunit beta) Succinyl-CoA synthetase (SCS) is a mitochondrial matrix enzyme that acts as a heterodimer, being composed of an invariant alpha subunit and a substrate-specific beta subunit. The protein encoded by this gene is an ATP-specific SCS beta subunit that dimerizes with the SCS alpha subunit to form SCS-A, an essential component of the tricarboxylic acid cycle. SCS-A hydrolyzes ATP to convert succinate to succinyl-CoA. Defects in this gene are a cause of myopathic mitochondrial DNA depletion syndrome. A pseudogene of this gene has been found on chromosome 6. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 13-47943043-T-C is Benign according to our data. Variant chr13-47943043-T-C is described in ClinVar as [Benign]. Clinvar id is 312259.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUCLA2	NM_003850.3	c.*328A>G		3_prime_UTR_variant	11/11	ENST00000646932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUCLA2	ENST00000646932.1	c.*328A>G		3_prime_UTR_variant	11/11		NM_003850.3	P1

Frequencies

GnomAD3 genomes AF: 0.0846 AC: 12879 AN: 152192 Hom.: 727 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0769

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.0235

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0726

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.109

GnomAD4 exome AF: 0.119 AC: 17892 AN: 150182 Hom.: 1311 Cov.: 0 AF XY: 0.126 AC XY: 10052 AN XY: 79936

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.0780

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.0147

Gnomad4 SAS exome AF: 0.185

Gnomad4 FIN exome AF: 0.0784

Gnomad4 NFE exome AF: 0.119

Gnomad4 OTH exome AF: 0.121

GnomAD4 genome AF: 0.0846 AC: 12888 AN: 152310 Hom.: 728 Cov.: 32 AF XY: 0.0847 AC XY: 6306 AN XY: 74494

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.0767

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.0237

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.0726

Gnomad4 NFE AF: 0.115

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0419 Hom.: 34

Bravo AF: 0.0810

Asia WGS AF: 0.138 AC: 479 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	11
Dann	Benign	0.79

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: rs13243; hg19: chr13-48517178;