Genetic Variant SUCLG1:c.98-11dupT (chr2-84449762-T-TA) – ACMG Classification: Likely_benign (-4 pts)

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0610

Publications

3 publications found

Variant links:

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

SUCLG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUCLG1	NM_003849.4 link	c.98-11dupT		intron_variant	Intron 1 of 8	ENST00000393868.7	NP_003840.2	P53597

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUCLG1	ENST00000393868.7 link	c.98-11_98-10insT		intron_variant	Intron 1 of 8	1	NM_003849.4	ENSP00000377446.2		P53597

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

154

AN:

90116

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000452

AC XY:

165

AN XY:

365156

show subpopulations

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

African (AFR)

AF:

0.000193

AC:

AN:

15578

American (AMR)

AF:

0.000102

AC:

AN:

19670

Ashkenazi Jewish (ASJ)

AF:

0.000123

AC:

AN:

16308

East Asian (EAS)

AF:

0.0000337

AC:

AN:

29662

South Asian (SAS)

AF:

0.000275

AC:

AN:

47250

European-Finnish (FIN)

AF:

0.000176

AC:

AN:

39668

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2278

European-Non Finnish (NFE)

AF:

0.000585

AC:

292

AN:

499210

Other (OTH)

AF:

0.000499

AC:

AN:

32072

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.288

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00171

AC:

154

AN:

90122

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

AN XY:

41578

show subpopulations

African (AFR)

AF:

0.000719

AC:

AN:

25026

American (AMR)

AF:

0.000359

AC:

AN:

8360

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2410

East Asian (EAS)

AF:

0.00

AC:

AN:

2968

South Asian (SAS)

AF:

0.00129

AC:

AN:

2330

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.00288

AC:

128

AN:

44420

Other (OTH)

AF:

0.000852

AC:

AN:

1174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

848

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over