chrX-19360381-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001001671.4(MAP3K15):c.*368G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 160,911 control chromosomes in the GnomAD database, including 5,133 homozygotes. There are 7,351 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 ( 4983 hom., 6669 hem., cov: 23)

Exomes 𝑓: 0.052 ( 150 hom. 682 hem. )

Consequence

MAP3K15
NM_001001671.4 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0340

Publications

2 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):

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

PDHA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant X-19360381-C-T is Benign according to our data. Variant chrX-19360381-C-T is described in ClinVar as Benign. ClinVar VariationId is 914462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP3K15	NM_001001671.4	MANE Select	c.*368G>A	3_prime_UTR	Exon 29 of 29	NP_001001671.3	Q6ZN16-1
PDHA1	NM_000284.4	MANE Select	c.*728C>T	3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
PDHA1	NM_001173454.2		c.*728C>T	3_prime_UTR	Exon 12 of 12	NP_001166925.1	P08559-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.*368G>A	3_prime_UTR	Exon 29 of 29	ENSP00000345629.4	Q6ZN16-1
PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*728C>T	3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
MAP3K15	ENST00000947404.1		c.*368G>A	3_prime_UTR	Exon 29 of 29	ENSP00000617463.1

Frequencies

GnomAD3 genomes

AF:

0.216

AC:

23959

AN:

111055

Hom.:

4980

Cov.:

show subpopulations

Gnomad AFR

AF:

0.655

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.0983

Gnomad ASJ

AF:

0.112

Gnomad EAS

AF:

0.00311

Gnomad SAS

AF:

0.138

Gnomad FIN

AF:

0.0321

Gnomad MID

AF:

0.208

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.196

GnomAD4 exome

AF:

0.0520

AC:

2588

AN:

49802

Hom.:

150

Cov.:

AF XY:

0.0612

AC XY:

682

AN XY:

11148

show subpopulations

African (AFR)

AF:

0.626

AC:

315

AN:

503

American (AMR)

AF:

0.0760

AC:

140

AN:

1841

Ashkenazi Jewish (ASJ)

AF:

0.0810

AC:

AN:

1123

East Asian (EAS)

AF:

0.00354

AC:

AN:

1131

South Asian (SAS)

AF:

0.118

AC:

649

AN:

5481

European-Finnish (FIN)

AF:

0.0324

AC:

AN:

3052

Middle Eastern (MID)

AF:

0.129

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.0312

AC:

1047

AN:

33576

Other (OTH)

AF:

0.0751

AC:

218

AN:

2901

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

152

228

304

380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.216

AC:

24005

AN:

111109

Hom.:

4983

Cov.:

AF XY:

0.200

AC XY:

6669

AN XY:

33369

show subpopulations

African (AFR)

AF:

0.655

AC:

19867

AN:

30315

American (AMR)

AF:

0.0982

AC:

1026

AN:

10453

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

294

AN:

2635

East Asian (EAS)

AF:

0.00312

AC:

AN:

3531

South Asian (SAS)

AF:

0.139

AC:

372

AN:

2672

European-Finnish (FIN)

AF:

0.0321

AC:

193

AN:

6004

Middle Eastern (MID)

AF:

0.205

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0344

AC:

1827

AN:

53097

Other (OTH)

AF:

0.194

AC:

292

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

380

760

1141

1521

1901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.110

Hom.:

1147

Bravo

AF:

0.243

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Pyruvate dehydrogenase E1-alpha deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.7

(source)

DANN

Benign

0.78

PhyloP100

0.034

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over