X-19360739-C-CTGAT

Variant names:

• chrX-19360739-C-CTGAT
• rs748635462
• NM_001001671.4:c.*6_*9dupATCA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001001671.4(MAP3K15):​c.*6_*9dupATCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000604 in 1,192,552 control chromosomes in the GnomAD database, including 1 homozygotes. There are 21 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.000059 (1 hom. 19 hem.)
• Consequence: MAP3K15 NM_001001671.4 3_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.00200

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant X-19360739-C-CTGAT is Benign according to our data. Variant chrX-19360739-C-CTGAT is described in ClinVar as [Likely_benign]. Clinvar id is 3060782.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K15	NM_001001671.4	c.*6_*9dupATCA		3_prime_UTR_variant	Exon 29 of 29	ENST00000338883.9	NP_001001671.3
PDHA1	NM_000284.4	c.*1089_*1092dupATTG		3_prime_UTR_variant	Exon 11 of 11	ENST00000422285.7	NP_000275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K15	ENST00000338883	c.*6_*9dupATCA		3_prime_UTR_variant	Exon 29 of 29	5	NM_001001671.4	ENSP00000345629.4
PDHA1	ENST00000422285.7	c.*1089_*1092dupATTG		3_prime_UTR_variant	Exon 11 of 11	1	NM_000284.4	ENSP00000394382.2

Frequencies

GnomAD3 genomes AF: 0.0000714 AC: 8 AN: 112055 Hom.: 0 Cov.: 24 AF XY: 0.0000584 AC XY: 2 AN XY: 34233

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000949

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000567 AC: 10 AN: 176414 Hom.: 0 AF XY: 0.0000321 AC XY: 2 AN XY: 62394

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0000771

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000228

GnomAD4 exome AF: 0.0000592 AC: 64 AN: 1080443 Hom.: 1 Cov.: 25 AF XY: 0.0000546 AC XY: 19 AN XY: 347789

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.0000753

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000435

Gnomad4 OTH exome AF: 0.000242

GnomAD4 genome AF: 0.0000714 AC: 8 AN: 112109 Hom.: 0 Cov.: 24 AF XY: 0.0000583 AC XY: 2 AN XY: 34297

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.0000948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000793

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PDHA1-related disorder Benign:1

Apr 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs748635462; hg19: chrX-19378857;