2-84449762-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAAA

Variant names:

• chr2-84449762-TAAAA-T
• rs56733272
• NM_003849.4:c.98-14_98-11delTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003849.4(SUCLG1):​c.98-14_98-11delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 783,810 control chromosomes in the GnomAD database, including 402 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (49 hom., cov: 0)
  • Exomes 𝑓: 0.23 (353 hom.)
• Consequence: SUCLG1 NM_003849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.72
• 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-84449762-TAAAA-T is Benign according to our data. Variant chr2-84449762-TAAAA-T is described in ClinVar as [Benign]. Clinvar id is 440310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLG1	NM_003849.4	c.98-14_98-11delTTTT		intron_variant	Intron 1 of 8	ENST00000393868.7	NP_003840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUCLG1	ENST00000393868.7	c.98-14_98-11delTTTT		intron_variant	Intron 1 of 8	1	NM_003849.4	ENSP00000377446.2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 1993 AN: 90144 Hom.: 49 Cov.: 0

Gnomad AFR AF: 0.0590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00788

Gnomad EAS AF: 0.0504

Gnomad SAS AF: 0.0209

Gnomad FIN AF: 0.00420

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00331

Gnomad OTH AF: 0.0214

GnomAD4 exome AF: 0.230 AC: 159610 AN: 693660 Hom.: 353 AF XY: 0.227 AC XY: 81725 AN XY: 360742

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

African (AFR) AF: 0.195 AC: 2979 AN: 15254

American (AMR) AF: 0.196 AC: 3809 AN: 19400

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 3278 AN: 16088

East Asian (EAS) AF: 0.240 AC: 7015 AN: 29210

South Asian (SAS) AF: 0.176 AC: 8149 AN: 46396

European-Finnish (FIN) AF: 0.153 AC: 5958 AN: 38974

Middle Eastern (MID) AF: 0.206 AC: 462 AN: 2240

European-Non Finnish (NFE) AF: 0.244 AC: 120604 AN: 494426

Other (OTH) AF: 0.232 AC: 7356 AN: 31672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0221 AC: 1991 AN: 90150 Hom.: 49 Cov.: 0 AF XY: 0.0228 AC XY: 948 AN XY: 41594

African (AFR) AF: 0.0589 AC: 1476 AN: 25044

American (AMR) AF: 0.0139 AC: 116 AN: 8362

Ashkenazi Jewish (ASJ) AF: 0.00788 AC: 19 AN: 2410

East Asian (EAS) AF: 0.0498 AC: 148 AN: 2970

South Asian (SAS) AF: 0.0210 AC: 49 AN: 2330

European-Finnish (FIN) AF: 0.00420 AC: 11 AN: 2618

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

European-Non Finnish (NFE) AF: 0.00331 AC: 147 AN: 44422

Other (OTH) AF: 0.0212 AC: 25 AN: 1178

Alfa AF: 0.000910 Hom.: 848

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 9 Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism

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: rs56733272; hg19: chr2-84676886;