2-84449762-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAA

Variant names:

• chr2-84449762-TAAAAA-T
• rs56733272
• NM_003849.4:c.98-15_98-11delTTTTT

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.98-15_98-11delTTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 767,600 control chromosomes in the GnomAD database, including 422 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (322 hom., cov: 0)
  • Exomes 𝑓: 0.16 (100 hom.)
• Consequence: SUCLG1 NM_003849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: 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-TAAAAA-T is Benign according to our data. Variant chr2-84449762-TAAAAA-T is described in ClinVar as [Benign]. Clinvar id is 403502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLG1	NM_003849.4	c.98-15_98-11delTTTTT		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.98-15_98-11delTTTTT		intron_variant	Intron 1 of 8	1	NM_003849.4	ENSP00000377446.2

Frequencies

GnomAD3 genomes AF: 0.0666 AC: 6005 AN: 90100 Hom.: 319 Cov.: 0

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.0193

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0627

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0858

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.0896

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0757

GnomAD4 exome AF: 0.155 AC: 105312 AN: 677494 Hom.: 100 AF XY: 0.155 AC XY: 54449 AN XY: 351572

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

African (AFR) AF: 0.192 AC: 2920 AN: 15180

American (AMR) AF: 0.165 AC: 3113 AN: 18836

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 2579 AN: 15716

East Asian (EAS) AF: 0.181 AC: 5093 AN: 28142

South Asian (SAS) AF: 0.148 AC: 6683 AN: 45250

European-Finnish (FIN) AF: 0.112 AC: 4309 AN: 38316

Middle Eastern (MID) AF: 0.180 AC: 393 AN: 2186

European-Non Finnish (NFE) AF: 0.155 AC: 75070 AN: 482992

Other (OTH) AF: 0.167 AC: 5152 AN: 30876

⚠️ 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: 0.0667 AC: 6013 AN: 90106 Hom.: 322 Cov.: 0 AF XY: 0.0697 AC XY: 2898 AN XY: 41562

African (AFR) AF: 0.166 AC: 4164 AN: 25022

American (AMR) AF: 0.0562 AC: 470 AN: 8364

Ashkenazi Jewish (ASJ) AF: 0.0627 AC: 151 AN: 2410

East Asian (EAS) AF: 0.0158 AC: 47 AN: 2966

South Asian (SAS) AF: 0.0855 AC: 199 AN: 2328

European-Finnish (FIN) AF: 0.0203 AC: 53 AN: 2614

Middle Eastern (MID) AF: 0.0979 AC: 19 AN: 194

European-Non Finnish (NFE) AF: 0.0182 AC: 808 AN: 44412

Other (OTH) AF: 0.0767 AC: 90 AN: 1174

Alfa AF: 0.00842 Hom.: 848

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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;