X-19360844-AAC-A

Position:

• chrX-19360844-AAC-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001001671.4(MAP3K15):​c.3858-13_3858-12del variant causes a splice polypyrimidine tract, intron 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: MAP3K15 NM_001001671.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.979

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

Verdict is Benign. Variant got -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 id is 445325.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0138 (14703/1062205) while in subpopulation NFE AF= 0.0164 (13362/816757). AF 95% confidence interval is 0.0161. There are 90 homozygotes in gnomad4_exome. There are 4474 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4	c.*1195_*1196del		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4	c.3858-13_3858-12del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000338883.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDHA1	ENST00000422285.7	c.*1195_*1196del		3_prime_UTR_variant	11/11	1	NM_000284.4	P1
MAP3K15	ENST00000338883.9	c.3858-13_3858-12del		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001001671.4	P1

Frequencies

GnomAD3 genomes AF: 0.00915 AC: 1026 AN: 112131 Hom.: 7 Cov.: 23 AF XY: 0.00799 AC XY: 274 AN XY: 34279

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

GnomAD3 exomes AF: 0.00828 AC: 1398 AN: 168882 Hom.: 6 AF XY: 0.00771 AC XY: 442 AN XY: 57292

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 SAS exome AF: 0.0000604

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

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00770

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.0143

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0107

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

Gnomad4 AFR AF: 0.00230

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.00870

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.00327

Alfa AF: 0.00939 Hom.: 68

Bravo AF: 0.00802

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Feb 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs202102403; hg19: chrX-19378962;