Genetic Variant NM_000284.4:c.57+2410dupT (chrX-19346494-A-AT) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 XL 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.:

AF XY:

0.00567

AC XY:

179

AN XY:

31558

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

GnomAD4 exome

AF:

0.00546

AC:

1655

AN:

303368

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

350

AN XY:

92854

show subpopulations

Gnomad4 AFR exome

AF:

0.0128

Gnomad4 AMR exome

AF:

0.00427

Gnomad4 ASJ exome

AF:

0.00136

Gnomad4 EAS exome

AF:

0.00123

Gnomad4 SAS exome

AF:

0.0351

Gnomad4 FIN exome

AF:

0.00305

Gnomad4 NFE exome

AF:

0.00312

Gnomad4 OTH exome

AF:

0.00442

GnomAD4 genome

AF:

0.00621

AC:

674

AN:

108600

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

183

AN XY:

31610

show subpopulations

Gnomad4 AFR

AF:

0.0136

Gnomad4 AMR

AF:

0.00306

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00115

Gnomad4 SAS

AF:

0.0419

Gnomad4 FIN

AF:

0.00214

Gnomad4 NFE

AF:

0.00169

Gnomad4 OTH

AF:

0.00473

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 22, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over