rs143030960

chr2-84443366-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP3 BP4_Moderate BP6 BS1

The NM_003849.4(SUCLG1):c.236G>A(p.Gly79Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,614,146 control chromosomes in the GnomAD database, including 2 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 0.00097 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: SUCLG1 NM_003849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 7.89

Genes affected

SUCLG1 (HGNC:11449): (succinate-CoA ligase GDP/ADP-forming subunit alpha) This gene encodes the alpha subunit of the heterodimeric enzyme succinate coenzyme A ligase. This enzyme is targeted to the mitochondria and catalyzes the conversion of succinyl CoA and ADP or GDP to succinate and ATP or GTP. Mutations in this gene are the cause of the metabolic disorder fatal infantile lactic acidosis and mitochondrial DNA depletion. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_003849.4
• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.16022444).
• BP6: Variant 2-84443366-C-T is Benign according to our data. Variant chr2-84443366-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203970.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000965 (147/152300) while in subpopulation NFE AF= 0.00137 (93/68020). AF 95% confidence interval is 0.00114. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUCLG1	NM_003849.4	c.236G>A	p.Gly79Asp	missense_variant	3/9	ENST00000393868.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUCLG1	ENST00000393868.7	c.236G>A	p.Gly79Asp	missense_variant	3/9	1	NM_003849.4	P1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00140 AC: 351 AN: 251356 Hom.: 0 AF XY: 0.00153 AC XY: 208 AN XY: 135836

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00143 AC: 2087 AN: 1461846 Hom.: 2 Cov.: 31 AF XY: 0.00142 AC XY: 1034 AN XY: 727214

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74470

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.000956

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 01, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2017	The p.Gly79Asp variant (rs143030960) has not been reported in the medical literature; although, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 203970). It is listed in the Genome Aggregation Database (gnomAD) browser with a frequency in Ashkenazi Jewish populations of 0.67% (identified in 68 out of 10,150 chromosomes). The glycine at codon 79 is highly conserved considering 11 species up to Baker’s yeast (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on SUCLG1 protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). However, based on the available information, the clinical significance of the p.Gly79Asp variant cannot be determined with certainty. -

Mitochondrial DNA depletion syndrome 9 Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 29, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 16, 2015

- -

Mitochondrial DNA depletion syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

SUCLG1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.47
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.16	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.99
MPC		0.29
ClinPred		0.22	T
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.92
gMVP		0.95

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: rs143030960; hg19: chr2-84670490;