X-19360666-C-A

Variant names:

• chrX-19360666-C-A
• rs1042456
• NM_001001671.4:c.*83G>T

Variant summary

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

The NM_001001671.4(MAP3K15):​c.*83G>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 0.0904 in 709,368 control chromosomes in the GnomAD database, including 8,548 homozygotes. There are 19,538 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5000 hom., 7078 hem., cov: 24)
  • Exomes 𝑓: 0.066 (3548 hom. 12460 hem.)
• Consequence: MAP3K15 NM_001001671.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.236
• Publications: 4 publications found

Genes affected

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]

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-19360666-C-A is Benign according to our data. Variant chrX-19360666-C-A is described in ClinVar as Benign. ClinVar VariationId is 914971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001671.4. 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
	MAP3K15	NM_001001671.4	MANE Select	c.*83G>T		3_prime_UTR	Exon 29 of 29	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_000284.4	MANE Select	c.*1013C>A		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.*1013C>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
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.*83G>T		3_prime_UTR	Exon 29 of 29	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*1013C>A		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000927253.1		c.*83G>T		3_prime_UTR	Exon 30 of 30	ENSP00000597312.1

Frequencies

GnomAD3 genomes AF: 0.217 AC: 24408 AN: 112235 Hom.: 4997 Cov.: 24

Gnomad AFR AF: 0.657

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0991

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.00497

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.211

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.193

GnomAD4 exome AF: 0.0664 AC: 39665 AN: 597079 Hom.: 3548 Cov.: 9 AF XY: 0.0722 AC XY: 12460 AN XY: 172687

African (AFR) AF: 0.671 AC: 10383 AN: 15484

American (AMR) AF: 0.0694 AC: 1787 AN: 25733

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 1726 AN: 15252

East Asian (EAS) AF: 0.00485 AC: 131 AN: 27017

South Asian (SAS) AF: 0.155 AC: 6135 AN: 39573

European-Finnish (FIN) AF: 0.0365 AC: 1356 AN: 37187

Middle Eastern (MID) AF: 0.173 AC: 513 AN: 2961

European-Non Finnish (NFE) AF: 0.0364 AC: 14753 AN: 404912

Other (OTH) AF: 0.0995 AC: 2881 AN: 28960

GnomAD4 genome AF: 0.218 AC: 24452 AN: 112289 Hom.: 5000 Cov.: 24 AF XY: 0.205 AC XY: 7078 AN XY: 34487

African (AFR) AF: 0.657 AC: 20222 AN: 30779

American (AMR) AF: 0.0990 AC: 1051 AN: 10616

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 298 AN: 2644

East Asian (EAS) AF: 0.00498 AC: 18 AN: 3611

South Asian (SAS) AF: 0.144 AC: 400 AN: 2783

European-Finnish (FIN) AF: 0.0323 AC: 198 AN: 6134

Middle Eastern (MID) AF: 0.208 AC: 44 AN: 212

European-Non Finnish (NFE) AF: 0.0347 AC: 1850 AN: 53291

Other (OTH) AF: 0.191 AC: 294 AN: 1539

Alfa AF: 0.0803 Hom.: 1691

Bravo AF: 0.243

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	-0.83
CADD	Benign	0.91
DANN	Benign	0.49
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: rs1042456; hg19: chrX-19378784;