Genetic Variant PDHA1:c.57+6A>T (chrX-19344100-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000284.4(PDHA1):c.57+6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000259 in 1,195,679 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 7 hem., cov: 24)

Exomes 𝑓: 0.000016 ( 0 hom. 6 hem. )

Consequence

PDHA1
NM_000284.4 splice_region, intron

Scores

Splicing: ADA: 0.00004013

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.117

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant X-19344100-A-T is Benign according to our data. Variant chrX-19344100-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 756440.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000127 (14/110410) while in subpopulation EAS AF = 0.000576 (2/3471). AF 95% confidence interval is 0.000203. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 7 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000284.4. 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+6A>T	splice_region intron	N/A	NP_000275.1	P08559-1
PDHA1	NM_001173454.2		c.57+6A>T	splice_region intron	N/A	NP_001166925.1	P08559-4
PDHA1	NM_001173455.2		c.57+6A>T	splice_region 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+6A>T	splice_region intron	N/A	ENSP00000394382.2	P08559-1
PDHA1	ENST00000947567.1		c.57+6A>T	splice_region intron	N/A	ENSP00000617626.1
PDHA1	ENST00000947577.1		c.57+6A>T	splice_region intron	N/A	ENSP00000617636.1

Frequencies

GnomAD3 genomes

AF:

0.000127

AC:

AN:

110410

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000576

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000673

GnomAD2 exomes

AF:

0.0000368

AC:

AN:

163015

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000271

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1085269

Hom.:

Cov.:

AF XY:

0.0000170

AC XY:

AN XY:

353329

show subpopulations

African (AFR)

AF:

0.000267

AC:

AN:

26180

American (AMR)

AF:

0.00

AC:

AN:

34609

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19178

East Asian (EAS)

AF:

0.0000999

AC:

AN:

30029

South Asian (SAS)

AF:

0.0000189

AC:

AN:

53033

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38669

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2885

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

835087

Other (OTH)

AF:

0.000110

AC:

AN:

45599

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

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:

0.000127

AC:

AN:

110410

Hom.:

Cov.:

AF XY:

0.000211

AC XY:

AN XY:

33132

show subpopulations

African (AFR)

AF:

0.000363

AC:

AN:

30293

American (AMR)

AF:

0.00

AC:

AN:

10577

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.000576

AC:

AN:

3471

South Asian (SAS)

AF:

0.00

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5862

Middle Eastern (MID)

AF:

0.00

AC:

AN:

231

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52534

Other (OTH)

AF:

0.000673

AC:

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

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:

0.000356

Hom.:

Bravo

AF:

0.000110

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Benign

0.81

PhyloP100

0.12

PromoterAI

0.12

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.010

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

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