X-19360861-A-C

Position:

chrX-19360861-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000284.4(PDHA1):c.*1208A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,105,890 control chromosomes in the GnomAD database, including 10 homozygotes. There are 1,106 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 5 hom., 75 hem., cov: 24)

Exomes 𝑓: 0.0035 ( 5 hom. 1031 hem. )

Consequence

PDHA1
NM_000284.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.217

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:

MAP3K15 (HGNC:31689): (mitogen-activated protein kinase kinase kinase 15) The protein encoded by this gene is a member of the mitogen-activated protein kinase (MAPK) family. These family members function in a protein kinase signal transduction cascade, where an activated MAPK kinase kinase (MAP3K) phosphorylates and activates a specific MAPK kinase (MAP2K), which then activates a specific MAPK. This MAP3K protein plays an essential role in apoptotic cell death triggered by cellular stresses. [provided by RefSeq, Jul 2010]

MAP3K15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant X-19360861-A-C is Benign according to our data. Variant chrX-19360861-A-C is described in ClinVar as [Benign]. Clinvar id is 914973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00256 (288/112341) while in subpopulation AMR AF= 0.00349 (37/10588). AF 95% confidence interval is 0.00261. There are 5 homozygotes in gnomad4. There are 75 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4 linkuse as main transcript	c.*1208A>C		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4 linkuse as main transcript	c.3858-28T>G		intron_variant		ENST00000338883.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7 linkuse as main transcript	c.*1208A>C		3_prime_UTR_variant	11/11	1	NM_000284.4	P1	P08559-1
MAP3K15	ENST00000338883.9 linkuse as main transcript	c.3858-28T>G		intron_variant		5	NM_001001671.4	P1	Q6ZN16-1

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

288

AN:

112289

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

AN XY:

34433

show subpopulations

Gnomad AFR

AF:

0.000518

Gnomad AMI

AF:

0.108

Gnomad AMR

AF:

0.00350

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00219

Gnomad FIN

AF:

0.000650

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00133

GnomAD3 exomes

AF:

0.00257

AC:

405

AN:

157812

Hom.:

AF XY:

0.00264

AC XY:

143

AN XY:

54176

show subpopulations

Gnomad AFR exome

AF:

0.000319

Gnomad AMR exome

AF:

0.00708

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00255

Gnomad FIN exome

AF:

0.000347

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00352

AC:

3502

AN:

993549

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

1031

AN XY:

282175

show subpopulations

Gnomad4 AFR exome

AF:

0.000344

Gnomad4 AMR exome

AF:

0.00818

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00238

Gnomad4 FIN exome

AF:

0.000202

Gnomad4 NFE exome

AF:

0.00393

Gnomad4 OTH exome

AF:

0.00357

GnomAD4 genome

AF:

0.00256

AC:

288

AN:

112341

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

AN XY:

34495

show subpopulations

Gnomad4 AFR

AF:

0.000517

Gnomad4 AMR

AF:

0.00349

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00220

Gnomad4 FIN

AF:

0.000650

Gnomad4 NFE

AF:

0.00281

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.00196

Hom.:

Bravo

AF:

0.00309

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.0

DANN

Benign

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

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

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