13-47973332-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003850.3(SUCLA2):c.595T>A(p.Ser199Thr) variant causes a missense change. The variant allele was found at a frequency of 0.787 in 1,612,708 control chromosomes in the GnomAD database, including 504,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41345 hom., cov: 31)
  • Exomes 𝑓: 0.79 (463110 hom.)
• Consequence: SUCLA2 NM_003850.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.74

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3342432E-6).
• BP6: Variant 13-47973332-A-T is Benign according to our data. Variant chr13-47973332-A-T is described in ClinVar as [Benign]. Clinvar id is 139360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-47973332-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUCLA2	NM_003850.3	c.595T>A	p.Ser199Thr	missense_variant	5/11	ENST00000646932.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUCLA2	ENST00000646932.1	c.595T>A	p.Ser199Thr	missense_variant	5/11		NM_003850.3	P1

Frequencies

GnomAD3 genomes AF: 0.730 AC: 110773 AN: 151840 Hom.: 41340 Cov.: 31

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.919

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.797

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.796

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.760

GnomAD3 exomes AF: 0.748 AC: 187942 AN: 251240 Hom.: 71475 AF XY: 0.750 AC XY: 101852 AN XY: 135798

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.635

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.792

Gnomad SAS exome AF: 0.633

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.818

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.793 AC: 1158709 AN: 1460752 Hom.: 463110 Cov.: 37 AF XY: 0.789 AC XY: 573638 AN XY: 726770

Gnomad4 AFR exome AF: 0.571

Gnomad4 AMR exome AF: 0.638

Gnomad4 ASJ exome AF: 0.783

Gnomad4 EAS exome AF: 0.780

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.791

Gnomad4 NFE exome AF: 0.820

Gnomad4 OTH exome AF: 0.783

GnomAD4 genome AF: 0.729 AC: 110808 AN: 151956 Hom.: 41345 Cov.: 31 AF XY: 0.727 AC XY: 54044 AN XY: 74292

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.797

Gnomad4 EAS AF: 0.798

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.796

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.760

Alfa AF: 0.785 Hom.: 12089

Bravo AF: 0.715

TwinsUK AF: 0.826 AC: 3064

ALSPAC AF: 0.841 AC: 3242

ESP6500AA AF: 0.594 AC: 2616

ESP6500EA AF: 0.818 AC: 7035

ExAC AF: 0.751 AC: 91230

Asia WGS AF: 0.689 AC: 2392 AN: 3476

EpiCase AF: 0.809

EpiControl AF: 0.806

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 19, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	16
Dann	Benign	0.15
DEOGEN2	Benign	0.19	T;T;.;.;.;T;T;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.23	N
MetaRNN	Benign	0.0000013	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.1	N;N;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.41	T
Polyphen		0.0	B;B;.;.;.;.;.;.;.
Vest4		0.018
MPC		0.26
ClinPred		0.012	T
GERP RS		4.6
Varity_R		0.070
gMVP		0.49

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: rs7320366; hg19: chr13-48547467;