2-84449762-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAAAAA

Variant names:

• chr2-84449762-T-TA
• rs56733272
• NM_003849.4:c.98-11dupT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_003849.4(SUCLG1):​c.98-11dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: SUCLG1 NM_003849.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610
• Publications: 3 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: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00171 (154/90122) while in subpopulation NFE AF = 0.00288 (128/44420). AF 95% confidence interval is 0.00248. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.98-11dupT		intron	N/A	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.98-11_98-10insT		intron	N/A	ENSP00000377446.2	P53597
	SUCLG1	ENST00000949558.1		c.98-11_98-10insT		intron	N/A	ENSP00000619617.1
	SUCLG1	ENST00000912793.1		c.98-11_98-10insT		intron	N/A	ENSP00000582852.1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 154 AN: 90116 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000720

Gnomad AMI AF: 0.00161

Gnomad AMR AF: 0.000359

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.000861

GnomAD4 exome AF: 0.000479 AC: 336 AN: 701696 Hom.: 0 Cov.: 0 AF XY: 0.000452 AC XY: 165 AN XY: 365156

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000193 AC: 3 AN: 15578

American (AMR) AF: 0.000102 AC: 2 AN: 19670

Ashkenazi Jewish (ASJ) AF: 0.000123 AC: 2 AN: 16308

East Asian (EAS) AF: 0.0000337 AC: 1 AN: 29662

South Asian (SAS) AF: 0.000275 AC: 13 AN: 47250

European-Finnish (FIN) AF: 0.000176 AC: 7 AN: 39668

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2278

European-Non Finnish (NFE) AF: 0.000585 AC: 292 AN: 499210

Other (OTH) AF: 0.000499 AC: 16 AN: 32072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00171 AC: 154 AN: 90122 Hom.: 0 Cov.: 0 AF XY: 0.00152 AC XY: 63 AN XY: 41578

African (AFR) AF: 0.000719 AC: 18 AN: 25026

American (AMR) AF: 0.000359 AC: 3 AN: 8360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2410

East Asian (EAS) AF: 0.00 AC: 0 AN: 2968

South Asian (SAS) AF: 0.00129 AC: 3 AN: 2330

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.00288 AC: 128 AN: 44420

Other (OTH) AF: 0.000852 AC: 1 AN: 1174

Alfa AF: 0.00 Hom.: 848

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56733272;

hg19: chr2-84676886;