NM_003849.4:c.959G>A

Variant names:

• chr2-84425470-C-T
• rs146834097
• NM_003849.4:c.959G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003849.4(SUCLG1):​c.959G>A​(p.Ser320Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SUCLG1 NM_003849.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.136
• Publications: 2 publications found

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]

SUCLG1 Gene-Disease associations (from GenCC):

• mitochondrial DNA depletion syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13183036).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUCLG1	NM_003849.4	MANE Select	c.959G>A	p.Ser320Asn	missense	Exon 8 of 9	NP_003840.2	P53597

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUCLG1	ENST00000393868.7	TSL:1 MANE Select	c.959G>A	p.Ser320Asn	missense	Exon 8 of 9	ENSP00000377446.2	P53597
	SUCLG1	ENST00000949558.1		c.986G>A	p.Ser329Asn	missense	Exon 9 of 10	ENSP00000619617.1
	SUCLG1	ENST00000912793.1		c.944G>A	p.Ser315Asn	missense	Exon 8 of 9	ENSP00000582852.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251292 AF XY: 0.0000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 88 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000149 AC: 166 AN: 1112010

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74356

African (AFR) AF: 0.0000483 AC: 2 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Mitochondrial DNA depletion syndrome 9 (2)
-	1	-	Mitochondrial DNA depletion syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.14
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.11
Sift	Benign	0.25	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.20
MVP		0.61
MPC		0.038
ClinPred		0.070	T
GERP RS		1.1
Varity_R		0.17
gMVP		0.48
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146834097; hg19: chr2-84652594;