X-19361030-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000284.4(PDHA1):​c.*1377G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 420,027 control chromosomes in the GnomAD database, including 5,723 homozygotes. There are 13,772 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4035 hom., 6649 hem., cov: 25)
  • Exomes 𝑓: 0.069 (1688 hom. 7123 hem.)
• Consequence: PDHA1 NM_000284.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.239
• Publications: 3 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant X-19361030-G-A is Benign according to our data. Variant chrX-19361030-G-A is described in ClinVar as Benign. ClinVar VariationId is 913015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

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>A		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	MAP3K15	NM_001001671.4	MANE Select	c.3858-197C>T		intron	N/A	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_001173454.2		c.*1377G>A		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>A		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.3858-197C>T		intron	N/A	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000947567.1		c.*1377G>A		3_prime_UTR	Exon 13 of 13	ENSP00000617626.1

Frequencies

GnomAD3 genomes AF: 0.198 AC: 22403 AN: 112918 Hom.: 4033 Cov.: 25

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0909

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.183

GnomAD4 exome AF: 0.0687 AC: 21109 AN: 307057 Hom.: 1688 Cov.: 4 AF XY: 0.0730 AC XY: 7123 AN XY: 97629

African (AFR) AF: 0.595 AC: 5505 AN: 9249

American (AMR) AF: 0.0810 AC: 881 AN: 10876

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 1048 AN: 9508

East Asian (EAS) AF: 0.00572 AC: 125 AN: 21853

South Asian (SAS) AF: 0.155 AC: 3414 AN: 21995

European-Finnish (FIN) AF: 0.0373 AC: 793 AN: 21277

Middle Eastern (MID) AF: 0.152 AC: 204 AN: 1341

European-Non Finnish (NFE) AF: 0.0379 AC: 7289 AN: 192305

Other (OTH) AF: 0.0992 AC: 1850 AN: 18653

GnomAD4 genome AF: 0.199 AC: 22442 AN: 112970 Hom.: 4035 Cov.: 25 AF XY: 0.189 AC XY: 6649 AN XY: 35146

African (AFR) AF: 0.590 AC: 18327 AN: 31064

American (AMR) AF: 0.0908 AC: 979 AN: 10780

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 298 AN: 2652

East Asian (EAS) AF: 0.00445 AC: 16 AN: 3598

South Asian (SAS) AF: 0.141 AC: 393 AN: 2791

European-Finnish (FIN) AF: 0.0306 AC: 192 AN: 6281

Middle Eastern (MID) AF: 0.199 AC: 43 AN: 216

European-Non Finnish (NFE) AF: 0.0344 AC: 1837 AN: 53354

Other (OTH) AF: 0.180 AC: 280 AN: 1553

Alfa AF: 0.192 Hom.: 1365

Bravo AF: 0.221

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.51
DANN	Benign	0.63
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs56039350; hg19: chrX-19379148;