2-84449762-TAAAAAAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr2-84449762-TAAAAAA-T
• rs56733272
• NM_003849.4:c.98-16_98-11delTTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_003849.4(SUCLG1):​c.98-16_98-11delTTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0492 in 773,678 control chromosomes in the GnomAD database, including 6 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.056 (6 hom.)
• Consequence: SUCLG1 NM_003849.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00142 (128/90120) while in subpopulation AFR AF = 0.00444 (111/25028). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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.98-16_98-11delTTTTTT		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.98-16_98-11delTTTTTT		intron	N/A	ENSP00000377446.2	P53597
	SUCLG1	ENST00000949558.1		c.98-16_98-11delTTTTTT		intron	N/A	ENSP00000619617.1
	SUCLG1	ENST00000912793.1		c.98-16_98-11delTTTTTT		intron	N/A	ENSP00000582852.1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 127 AN: 90114 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000838

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000336

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.000382

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000675

Gnomad OTH AF: 0.00172

GnomAD4 exome AF: 0.0555 AC: 37959 AN: 683558 Hom.: 6 AF XY: 0.0552 AC XY: 19606 AN XY: 355064

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

African (AFR) AF: 0.0835 AC: 1268 AN: 15192

American (AMR) AF: 0.0636 AC: 1210 AN: 19026

Ashkenazi Jewish (ASJ) AF: 0.0644 AC: 1015 AN: 15756

East Asian (EAS) AF: 0.0658 AC: 1872 AN: 28448

South Asian (SAS) AF: 0.0566 AC: 2591 AN: 45802

European-Finnish (FIN) AF: 0.0408 AC: 1579 AN: 38680

Middle Eastern (MID) AF: 0.0670 AC: 148 AN: 2210

European-Non Finnish (NFE) AF: 0.0540 AC: 26311 AN: 487220

Other (OTH) AF: 0.0629 AC: 1965 AN: 31224

⚠️ 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: 0.00142 AC: 128 AN: 90120 Hom.: 0 Cov.: 0 AF XY: 0.00135 AC XY: 56 AN XY: 41572

African (AFR) AF: 0.00444 AC: 111 AN: 25028

American (AMR) AF: 0.000837 AC: 7 AN: 8362

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

East Asian (EAS) AF: 0.000337 AC: 1 AN: 2968

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

European-Finnish (FIN) AF: 0.000382 AC: 1 AN: 2618

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

European-Non Finnish (NFE) AF: 0.0000675 AC: 3 AN: 44414

Other (OTH) AF: 0.00170 AC: 2 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		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56733272; hg19: chr2-84676886;