X-19360712-G-A

Position:

chrX-19360712-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001001671.4(MAP3K15):c.*37C>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 0.0797 in 1,048,618 control chromosomes in the GnomAD database, including 10,344 homozygotes. There are 24,979 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 ( 5003 hom., 6902 hem., cov: 23)

Exomes 𝑓: 0.063 ( 5341 hom. 18077 hem. )

Consequence

MAP3K15
NM_001001671.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.160

Variant links:

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]

PDHA1 links:

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]

MAP3K15 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant X-19360712-G-A is Benign according to our data. Variant chrX-19360712-G-A is described in ClinVar as [Benign]. Clinvar id is 914972.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDHA1	NM_000284.4 linkuse as main transcript	c.*1059G>A		3_prime_UTR_variant	11/11	ENST00000422285.7
MAP3K15	NM_001001671.4 linkuse as main transcript	c.*37C>T		3_prime_UTR_variant	29/29	ENST00000338883.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP3K15	ENST00000338883.9 linkuse as main transcript	c.*37C>T		3_prime_UTR_variant	29/29	5	NM_001001671.4	P1	Q6ZN16-1
PDHA1	ENST00000422285.7 linkuse as main transcript	c.*1059G>A		3_prime_UTR_variant	11/11	1	NM_000284.4	P1	P08559-1

Frequencies

GnomAD3 genomes

AF:

0.217

AC:

24228

AN:

111755

Hom.:

5000

Cov.:

AF XY:

0.202

AC XY:

6863

AN XY:

33941

show subpopulations

Gnomad AFR

AF:

0.657

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.0993

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.00530

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.209

Gnomad NFE

AF:

0.0345

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.0985

AC:

16881

AN:

171301

Hom.:

2505

AF XY:

0.0847

AC XY:

4942

AN XY:

58347

show subpopulations

Gnomad AFR exome

AF:

0.672

Gnomad AMR exome

AF:

0.0590

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.00282

Gnomad SAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.0335

Gnomad NFE exome

AF:

0.0365

Gnomad OTH exome

AF:

0.0822

GnomAD4 exome

AF:

0.0633

AC:

59346

AN:

936807

Hom.:

5341

Cov.:

AF XY:

0.0683

AC XY:

18077

AN XY:

264807

show subpopulations

Gnomad4 AFR exome

AF:

0.682

Gnomad4 AMR exome

AF:

0.0674

Gnomad4 ASJ exome

AF:

0.111

Gnomad4 EAS exome

AF:

0.00497

Gnomad4 SAS exome

AF:

0.154

Gnomad4 FIN exome

AF:

0.0359

Gnomad4 NFE exome

AF:

0.0363

Gnomad4 OTH exome

AF:

0.0984

GnomAD4 genome

AF:

0.217

AC:

24274

AN:

111811

Hom.:

5003

Cov.:

AF XY:

0.203

AC XY:

6902

AN XY:

34007

show subpopulations

Gnomad4 AFR

AF:

0.657

Gnomad4 AMR

AF:

0.0992

Gnomad4 ASJ

AF:

0.112

Gnomad4 EAS

AF:

0.00532

Gnomad4 SAS

AF:

0.142

Gnomad4 FIN

AF:

0.0313

Gnomad4 NFE

AF:

0.0345

Gnomad4 OTH

AF:

0.189

Alfa

AF:

0.0645

Hom.:

2684

Bravo

AF:

0.243

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.33

DANN

Benign

0.71

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over