rs202102403

Variant names:

• chrX-19360844-AAC-A
• rs202102403
• NM_000284.4:c.*1195_*1196delCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000284.4(PDHA1):​c.*1195_*1196delCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,174,388 control chromosomes in the GnomAD database, including 97 homozygotes. There are 4,748 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (7 hom., 274 hem., cov: 23)
  • Exomes 𝑓: 0.014 (90 hom. 4474 hem.)
• Consequence: PDHA1 NM_000284.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.979
• 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 -10 ACMG points.

• BP6: Variant X-19360844-AAC-A is Benign according to our data. Variant chrX-19360844-AAC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 445325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00915 (1026/112183) while in subpopulation NFE AF = 0.0151 (802/53218). AF 95% confidence interval is 0.0142. There are 7 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 XL,AR 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.*1195_*1196delCA		3_prime_UTR	Exon 11 of 11	NP_000275.1
	MAP3K15	NM_001001671.4	MANE Select	c.3858-13_3858-12delGT		intron	N/A	NP_001001671.3
	PDHA1	NM_001173454.2		c.*1195_*1196delCA		3_prime_UTR	Exon 12 of 12	NP_001166925.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*1195_*1196delCA		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.3858-13_3858-12delGT		intron	N/A	ENSP00000345629.4
	PDHA1	ENST00000947567.1		c.*1195_*1196delCA		3_prime_UTR	Exon 13 of 13	ENSP00000617626.1

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1026 AN: 112131 Hom.: 7 Cov.: 23

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00292

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.00870

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.00332

GnomAD2 exomes AF: 0.00828 AC: 1398 AN: 168882 AF XY: 0.00771

Gnomad AFR exome AF: 0.00188

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00650

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.0138 AC: 14703 AN: 1062205 Hom.: 90 AF XY: 0.0135 AC XY: 4474 AN XY: 332309

African (AFR) AF: 0.00119 AC: 30 AN: 25188

American (AMR) AF: 0.00318 AC: 100 AN: 31441

Ashkenazi Jewish (ASJ) AF: 0.00770 AC: 143 AN: 18575

East Asian (EAS) AF: 0.00 AC: 0 AN: 29915

South Asian (SAS) AF: 0.0000584 AC: 3 AN: 51407

European-Finnish (FIN) AF: 0.0143 AC: 574 AN: 40115

Middle Eastern (MID) AF: 0.00248 AC: 10 AN: 4032

European-Non Finnish (NFE) AF: 0.0164 AC: 13362 AN: 816757

Other (OTH) AF: 0.0107 AC: 481 AN: 44775

GnomAD4 genome AF: 0.00915 AC: 1026 AN: 112183 Hom.: 7 Cov.: 23 AF XY: 0.00798 AC XY: 274 AN XY: 34341

African (AFR) AF: 0.00230 AC: 71 AN: 30913

American (AMR) AF: 0.00425 AC: 45 AN: 10578

Ashkenazi Jewish (ASJ) AF: 0.00870 AC: 23 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2730

European-Finnish (FIN) AF: 0.0126 AC: 77 AN: 6126

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.0151 AC: 802 AN: 53218

Other (OTH) AF: 0.00327 AC: 5 AN: 1527

Alfa AF: 0.00939 Hom.: 68

Bravo AF: 0.00802

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.98
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs202102403; hg19: chrX-19378962;