2-84449762-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

• chr2-84449762-TAAA-T
• rs56733272
• NM_003849.4:c.98-13_98-11delTTT

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.98-13_98-11delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 772,734 control chromosomes in the GnomAD database, including 28,306 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (25329 hom., cov: 0)
  • Exomes 𝑓: 0.34 (2977 hom.)
• Consequence: SUCLG1 NM_003849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: 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-TAAA-T is Benign according to our data. Variant chr2-84449762-TAAA-T is described in ClinVar as [Benign]. Clinvar id is 337162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLG1	NM_003849.4	c.98-13_98-11delTTT		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.98-13_98-11delTTT		intron_variant	Intron 1 of 8	1	NM_003849.4	ENSP00000377446.2

Frequencies

GnomAD3 genomes AF: 0.739 AC: 66527 AN: 90048 Hom.: 25340 Cov.: 0

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.861

Gnomad EAS AF: 0.802

Gnomad SAS AF: 0.818

Gnomad FIN AF: 0.871

Gnomad MID AF: 0.748

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.746

GnomAD4 exome AF: 0.336 AC: 229157 AN: 682680 Hom.: 2977 AF XY: 0.330 AC XY: 116881 AN XY: 354582

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

African (AFR) AF: 0.240 AC: 3599 AN: 14982

American (AMR) AF: 0.264 AC: 4975 AN: 18868

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 4233 AN: 15750

East Asian (EAS) AF: 0.321 AC: 9165 AN: 28518

South Asian (SAS) AF: 0.235 AC: 10555 AN: 44944

European-Finnish (FIN) AF: 0.219 AC: 8488 AN: 38698

Middle Eastern (MID) AF: 0.296 AC: 652 AN: 2206

European-Non Finnish (NFE) AF: 0.363 AC: 177258 AN: 487692

Other (OTH) AF: 0.330 AC: 10232 AN: 31022

⚠️ 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: 0.739 AC: 66508 AN: 90054 Hom.: 25329 Cov.: 0 AF XY: 0.734 AC XY: 30496 AN XY: 41564

African (AFR) AF: 0.473 AC: 11858 AN: 25092

American (AMR) AF: 0.816 AC: 6837 AN: 8378

Ashkenazi Jewish (ASJ) AF: 0.861 AC: 2070 AN: 2404

East Asian (EAS) AF: 0.802 AC: 2384 AN: 2974

South Asian (SAS) AF: 0.818 AC: 1890 AN: 2310

European-Finnish (FIN) AF: 0.871 AC: 2275 AN: 2612

Middle Eastern (MID) AF: 0.730 AC: 143 AN: 196

European-Non Finnish (NFE) AF: 0.851 AC: 37695 AN: 44308

Other (OTH) AF: 0.743 AC: 865 AN: 1164

Alfa AF: 0.518 Hom.: 848

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial DNA depletion syndrome 9 Benign:3

Mar 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Oct 12, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial DNA depletion syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.061
Mutation Taster		=100/0	polymorphism (auto)

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;