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_001173454.2(PDHA1):c.58-6dupT variant causes a splice region, 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. 1/1 splice prediction tools predict no significant impact on normal splicing. 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_001173454.2 splice_region, 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):

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173454.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDHA1	NM_000284.4	MANE Select	c.57+2410dupT	intron	N/A	NP_000275.1	P08559-1
PDHA1	NM_001173454.2		c.58-6dupT	splice_region intron	N/A	NP_001166925.1	P08559-4
PDHA1	NM_001173455.2		c.57+2410dupT	intron	N/A	NP_001166926.1	P08559-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.57+2400_57+2401insT	intron	N/A	ENSP00000394382.2	P08559-1
PDHA1	ENST00000947567.1		c.142-16_142-15insT	intron	N/A	ENSP00000617626.1
PDHA1	ENST00000947577.1		c.58-16_58-15insT	intron	N/A	ENSP00000617636.1

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), 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

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00621

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

Age Distribution

Genome Het

Genome Hom

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:

0.00417

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over