chrX-19344067-C-T

Variant names:

• chrX-19344067-C-T
• rs1425138915
• NM_000284.4:c.30C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000284.4(PDHA1):​c.30C>T​(p.Arg10Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,884 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: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: PDHA1 NM_000284.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.128
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant X-19344067-C-T is Benign according to our data. Variant chrX-19344067-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1086532.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.128 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.30C>T	p.Arg10Arg	synonymous	Exon 1 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.30C>T	p.Arg10Arg	synonymous	Exon 1 of 12	NP_001166925.1	P08559-4
	PDHA1	NM_001173455.2		c.30C>T	p.Arg10Arg	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.30C>T	p.Arg10Arg	synonymous	Exon 1 of 11	ENSP00000394382.2	P08559-1
	PDHA1	ENST00000947567.1		c.30C>T	p.Arg10Arg	synonymous	Exon 1 of 13	ENSP00000617626.1
	PDHA1	ENST00000947577.1		c.30C>T	p.Arg10Arg	synonymous	Exon 1 of 12	ENSP00000617636.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000577 AC: 1 AN: 173334 AF XY: 0.0000161

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: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093884 Hom.: 0 Cov.: 29 AF XY: 0.00000277 AC XY: 1 AN XY: 361020

African (AFR) AF: 0.00 AC: 0 AN: 26315

American (AMR) AF: 0.00 AC: 0 AN: 35124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19320

East Asian (EAS) AF: 0.00 AC: 0 AN: 30164

South Asian (SAS) AF: 0.00 AC: 0 AN: 53758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39477

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2999

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840847

Other (OTH) AF: 0.00 AC: 0 AN: 45880

GnomAD4 genome Cov.: 25

Alfa AF: 0.000102 Hom.: 1

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	-0.28
CADD	Benign	10
DANN	Uncertain	0.98
PhyloP100		-0.13
PromoterAI		0.089	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs1425138915; hg19: chrX-19362185;