NM_000284.4:c.*1376C>G

Variant names:

• chrX-19361029-C-G
• rs963546680
• NM_000284.4:c.*1376C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000284.4(PDHA1):​c.*1376C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000714 in 420,406 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes 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: 𝑓 0.000018 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000033 (0 hom. 0 hem.)
• Consequence: PDHA1 NM_000284.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS2: High Hemizygotes in GnomAd4 at 2 AR,XL gene

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.*1376C>G		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	MAP3K15	NM_001001671.4	MANE Select	c.3858-196G>C		intron	N/A	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_001173454.2		c.*1376C>G		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.*1376C>G		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.3858-196G>C		intron	N/A	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000947567.1		c.*1376C>G		3_prime_UTR	Exon 13 of 13	ENSP00000617626.1

Frequencies

GnomAD3 genomes AF: 0.0000176 AC: 2 AN: 113360 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000326 AC: 1 AN: 307046 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 97326

⚠️ 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: 9280

American (AMR) AF: 0.0000920 AC: 1 AN: 10865

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9481

East Asian (EAS) AF: 0.00 AC: 0 AN: 21825

South Asian (SAS) AF: 0.00 AC: 0 AN: 21933

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1352

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 192393

Other (OTH) AF: 0.00 AC: 0 AN: 18629

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000176 AC: 2 AN: 113360 Hom.: 0 Cov.: 24 AF XY: 0.0000564 AC XY: 2 AN XY: 35490

African (AFR) AF: 0.0000640 AC: 2 AN: 31251

American (AMR) AF: 0.00 AC: 0 AN: 10799

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3630

South Asian (SAS) AF: 0.00 AC: 0 AN: 2801

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6317

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53440

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.57
PhyloP100		-1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs963546680; hg19: chrX-19379147;