rs796052053

Variant names:

• chr2-84459230-T-A
• rs796052053
• NM_003849.4:c.40A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-84459230-T-A
• chr2-84459230-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM5 PP5 BP4

The NM_003849.4(SUCLG1):​c.40A>T​(p.Met14Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000858 in 1,398,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M14V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: SUCLG1 NM_003849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.93
• Publications: 6 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet, PanelApp Australia
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-84459230-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203978.
• PP5: Variant 2-84459230-T-A is Pathogenic according to our data. Variant chr2-84459230-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 561158.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35133097). . Strength limited to SUPPORTING due to the PP5.

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.40A>T	p.Met14Leu	missense	Exon 1 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.40A>T	p.Met14Leu	missense	Exon 1 of 9	ENSP00000377446.2	P53597
	SUCLG1	ENST00000949558.1		c.40A>T	p.Met14Leu	missense	Exon 1 of 10	ENSP00000619617.1
	SUCLG1	ENST00000912793.1		c.40A>T	p.Met14Leu	missense	Exon 1 of 9	ENSP00000582852.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000586 AC: 9 AN: 153666 AF XY: 0.0000491

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000858 AC: 12 AN: 1398350 Hom.: 0 Cov.: 31 AF XY: 0.00000725 AC XY: 5 AN XY: 689700

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.000308 AC: 11 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078814

Other (OTH) AF: 0.00 AC: 0 AN: 57982

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Mitochondrial DNA depletion syndrome 9 (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.54
Sift	Benign	0.59	T
Sift4G	Benign	1.0	T
Polyphen		0.17	B
Vest4		0.43
MutPred		0.34		Loss of catalytic residue at M14 (P = 0.0699)
MVP		0.77
MPC		0.038
ClinPred		0.37	T
GERP RS		5.2
PromoterAI		-0.26	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.76
Mutation Taster		=34/66	disease causing (ClinVar)

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: rs796052053; hg19: chr2-84686354;