chrX-19360382-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001001671.4(MAP3K15):c.*367C>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 0.000383 in 159,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00052 ( 0 hom. 6 hem. )

Consequence

MAP3K15
NM_001001671.4 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.60

Publications

0 publications found

Variant links:

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]

MAP3K15 links:

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):

Leigh syndrome
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
pyruvate dehydrogenase E1-alpha deficiency
Inheritance: XL, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PDHA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BS2

High Hemizygotes in GnomAd4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP3K15	NM_001001671.4 link	c.*367C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000338883.9	NP_001001671.3	Q6ZN16-1
PDHA1	NM_000284.4 link	c.*729G>A		3_prime_UTR_variant	Exon 11 of 11	ENST00000422285.7	NP_000275.1	P08559-1A0A024RBX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP3K15	ENST00000338883.9 link	c.*367C>T		3_prime_UTR_variant	Exon 29 of 29	5	NM_001001671.4	ENSP00000345629.4		Q6ZN16-1
PDHA1	ENST00000422285.7 link	c.*729G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_000284.4	ENSP00000394382.2		P08559-1

Frequencies

GnomAD3 genomes

AF:

0.000314

AC:

AN:

111357

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000958

Gnomad ASJ

AF:

0.000380

Gnomad EAS

AF:

0.000283

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000168

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000546

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000523

AC:

AN:

47820

Hom.:

Cov.:

AF XY:

0.000575

AC XY:

AN XY:

10434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

535

American (AMR)

AF:

0.000557

AC:

AN:

1795

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1098

East Asian (EAS)

AF:

0.00284

AC:

AN:

1055

South Asian (SAS)

AF:

0.000381

AC:

AN:

5245

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2923

Middle Eastern (MID)

AF:

0.00

AC:

AN:

177

European-Non Finnish (NFE)

AF:

0.000528

AC:

AN:

32212

Other (OTH)

AF:

0.000719

AC:

AN:

2780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.578

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000323

AC:

AN:

111407

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

33657

show subpopulations

African (AFR)

AF:

0.0000652

AC:

AN:

30672

American (AMR)

AF:

0.0000957

AC:

AN:

10451

Ashkenazi Jewish (ASJ)

AF:

0.000380

AC:

AN:

2635

East Asian (EAS)

AF:

0.000284

AC:

AN:

3523

South Asian (SAS)

AF:

0.000374

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.000168

AC:

AN:

5967

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000546

AC:

AN:

53070

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000329

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pyruvate dehydrogenase E1-alpha deficiency

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.99

(source)

DANN

Benign

0.43

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over