chrX-19344055-C-T

Variant names:

• chrX-19344055-C-T
• rs1275009783
• NM_000284.4:c.18C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_000284.4(PDHA1):​c.18C>T​(p.Ala6Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,094,016 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: PDHA1 NM_000284.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.822
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant X-19344055-C-T is Benign according to our data. Variant chrX-19344055-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1582407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.822 with no splicing effect.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	NM_000284.4	MANE Select	c.18C>T	p.Ala6Ala	synonymous	Exon 1 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.18C>T	p.Ala6Ala	synonymous	Exon 1 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.18C>T	p.Ala6Ala	synonymous	Exon 1 of 11	NP_001166926.1	P08559-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.18C>T	p.Ala6Ala	synonymous	Exon 1 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.18C>T	p.Ala6Ala	synonymous	Exon 1 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.18C>T	p.Ala6Ala	synonymous	Exon 1 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00 AC: 0 AN: 174076 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1094016 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 361120

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

African (AFR) AF: 0.00 AC: 0 AN: 26313

American (AMR) AF: 0.00 AC: 0 AN: 35138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19315

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.00 AC: 0 AN: 53766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39457

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3005

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 840984

Other (OTH) AF: 0.00 AC: 0 AN: 45879

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00536222), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	6.8
DANN	Benign	0.96
PhyloP100		-0.82
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

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

Other links and lift over

dbSNP: rs1275009783; hg19: chrX-19362173; COSMIC: COSV63327958;