X-19361030-G-T

Variant names:

• chrX-19361030-G-T
• rs56039350
• NM_000284.4:c.*1377G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000284.4(PDHA1):​c.*1377G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 307,160 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000033 (0 hom. 0 hem.)
• Consequence: PDHA1 NM_000284.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• 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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.*1377G>T		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	MAP3K15	NM_001001671.4	MANE Select	c.3858-197C>A		intron	N/A	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_001173454.2		c.*1377G>T		3_prime_UTR	Exon 12 of 12	NP_001166925.1	P08559-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*1377G>T		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.3858-197C>A		intron	N/A	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000947567.1		c.*1377G>T		3_prime_UTR	Exon 13 of 13	ENSP00000617626.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000326 AC: 1 AN: 307160 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 97638

African (AFR) AF: 0.00 AC: 0 AN: 9270

American (AMR) AF: 0.00 AC: 0 AN: 10882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9513

East Asian (EAS) AF: 0.00 AC: 0 AN: 21853

South Asian (SAS) AF: 0.00 AC: 0 AN: 22013

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21283

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1343

European-Non Finnish (NFE) AF: 0.00000520 AC: 1 AN: 192346

Other (OTH) AF: 0.00 AC: 0 AN: 18657

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.40
DANN	Benign	0.64
PhyloP100		-0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.60		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.60		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56039350; hg19: chrX-19379148;