NM_000284.4:c.1195_1196delCA

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_000284.4(PDHA1):c.*1195_*1196delCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 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

PDHA1
NM_000284.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.979

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 445325.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00915 (1026/112183) while in subpopulation NFE AF = 0.0151 (802/53218). AF 95% confidence interval is 0.0142. There are 7 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 XL,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDHA1	NM_000284.4 link	c.1195_1196delCA		3_prime_UTR_variant	Exon 11 of 11	ENST00000422285.7	NP_000275.1	P08559-1A0A024RBX9
MAP3K15	NM_001001671.4 link	c.3858-13_3858-12delGT		intron_variant	Intron 28 of 28	ENST00000338883.9	NP_001001671.3	Q6ZN16-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDHA1	ENST00000422285.7 link	c.1195_1196delCA		3_prime_UTR_variant	Exon 11 of 11	1	NM_000284.4	ENSP00000394382.2		P08559-1
MAP3K15	ENST00000338883.9 link	c.3858-13_3858-12delGT		intron_variant	Intron 28 of 28	5	NM_001001671.4	ENSP00000345629.4		Q6ZN16-1

Frequencies

GnomAD3 genomes

AF:

0.00915

AC:

1026

AN:

112131

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00828

AC:

1398

AN:

168882

AF XY:

0.00771

show subpopulations

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 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.:

AF XY:

0.0135

AC XY:

4474

AN XY:

332309

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

25188

American (AMR)

AF:

0.00318

AC:

100

AN:

31441

Ashkenazi Jewish (ASJ)

AF:

0.00770

AC:

143

AN:

18575

East Asian (EAS)

AF:

0.00

AC:

AN:

29915

South Asian (SAS)

AF:

0.0000584

AC:

AN:

51407

European-Finnish (FIN)

AF:

0.0143

AC:

574

AN:

40115

Middle Eastern (MID)

AF:

0.00248

AC:

AN:

4032

European-Non Finnish (NFE)

AF:

0.0164

AC:

13362

AN:

816757

Other (OTH)

AF:

0.0107

AC:

481

AN:

44775

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

477

954

1430

1907

2384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

514

1028

1542

2056

2570

<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:

0.00915

AC:

1026

AN:

112183

Hom.:

Cov.:

AF XY:

0.00798

AC XY:

274

AN XY:

34341

show subpopulations

African (AFR)

AF:

0.00230

AC:

AN:

30913

American (AMR)

AF:

0.00425

AC:

AN:

10578

Ashkenazi Jewish (ASJ)

AF:

0.00870

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.0126

AC:

AN:

6126

Middle Eastern (MID)

AF:

0.00457

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0151

AC:

802

AN:

53218

Other (OTH)

AF:

0.00327

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00939

Hom.:

Bravo

AF:

0.00802

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 20, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.98

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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