X-19346494-AT-ATT

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000284.4(PDHA1):c.57+2410dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 411,968 control chromosomes in the GnomAD database, including 19 homozygotes. There are 533 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 3 hom., 183 hem., cov: 23)

Exomes 𝑓: 0.0055 ( 16 hom. 350 hem. )

Consequence

PDHA1
NM_000284.4 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.286

Publications

0 publications found

Variant links:

Genes affected

PDHA1 (HGNC:8806): (pyruvate dehydrogenase E1 subunit alpha 1) The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

PDHA1 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
pyruvate dehydrogenase E1-alpha deficiency
Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDHA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP6

Variant X-19346494-A-AT is Benign according to our data. Variant chrX-19346494-A-AT is described in ClinVar as [Likely_benign]. Clinvar id is 445393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00621 (674/108600) while in subpopulation SAS AF = 0.0419 (107/2555). AF 95% confidence interval is 0.0354. There are 3 homozygotes in GnomAd4. There are 183 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4 link	c.57+2410dupT		intron_variant	Intron 1 of 10	ENST00000422285.7	NP_000275.1	P08559-1A0A024RBX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7 link	c.57+2400_57+2401insT		intron_variant	Intron 1 of 10	1	NM_000284.4	ENSP00000394382.2		P08559-1

Frequencies

GnomAD3 genomes

AF:

0.00617

AC:

670

AN:

108558

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.0271

Gnomad AMR

AF:

0.00306

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00114

Gnomad SAS

AF:

0.0420

Gnomad FIN

AF:

0.00214

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.0127

AC:

458

AN:

36099

AF XY:

0.00650

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.00669

Gnomad ASJ exome

AF:

0.00390

Gnomad EAS exome

AF:

0.0102

Gnomad FIN exome

AF:

0.00505

Gnomad NFE exome

AF:

0.00645

Gnomad OTH exome

AF:

0.0124

GnomAD4 exome

AF:

0.00546

AC:

1655

AN:

303368

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

350

AN XY:

92854

show subpopulations

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

African (AFR)

AF:

0.0128

AC:

102

AN:

7957

American (AMR)

AF:

0.00427

AC:

AN:

20139

Ashkenazi Jewish (ASJ)

AF:

0.00136

AC:

AN:

11064

East Asian (EAS)

AF:

0.00123

AC:

AN:

19505

South Asian (SAS)

AF:

0.0351

AC:

707

AN:

20114

European-Finnish (FIN)

AF:

0.00305

AC:

AN:

20997

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

2471

European-Non Finnish (NFE)

AF:

0.00312

AC:

573

AN:

183469

Other (OTH)

AF:

0.00442

AC:

AN:

17652

⚠️ 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: 0.376

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00621

AC:

674

AN:

108600

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

183

AN XY:

31610

show subpopulations

African (AFR)

AF:

0.0136

AC:

407

AN:

29854

American (AMR)

AF:

0.00306

AC:

AN:

10132

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2582

East Asian (EAS)

AF:

0.00115

AC:

AN:

3493

South Asian (SAS)

AF:

0.0419

AC:

107

AN:

2555

European-Finnish (FIN)

AF:

0.00214

AC:

AN:

5598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.00169

AC:

AN:

52029

Other (OTH)

AF:

0.00473

AC:

AN:

1480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

102

128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00417

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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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X-19346494-AT-ATT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over