NM_001001671.4:c.*6_*9dupATCA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -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 VariationId is 3060782.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K15	NM_001001671.4	MANE Select	c.*6_*9dupATCA		3_prime_UTR	Exon 29 of 29	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_000284.4	MANE Select	c.*1089_*1092dupATTG		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	PDHA1	NM_001173454.2		c.*1089_*1092dupATTG		3_prime_UTR	Exon 12 of 12	NP_001166925.1	P08559-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.*6_*9dupATCA		3_prime_UTR	Exon 29 of 29	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*1089_*1092dupATTG		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000927253.1		c.*6_*9dupATCA		3_prime_UTR	Exon 30 of 30	ENSP00000597312.1

Frequencies

GnomAD3 genomes AF: 0.0000714 AC: 8 AN: 112055 Hom.: 0 Cov.: 24

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

GnomAD2 exomes AF: 0.0000567 AC: 10 AN: 176414 AF XY: 0.0000321

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 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

African (AFR) AF: 0.000270 AC: 7 AN: 25892

American (AMR) AF: 0.000145 AC: 5 AN: 34413

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19188

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30083

South Asian (SAS) AF: 0.0000753 AC: 4 AN: 53114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4085

European-Non Finnish (NFE) AF: 0.0000435 AC: 36 AN: 827844

Other (OTH) AF: 0.000242 AC: 11 AN: 45460

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

African (AFR) AF: 0.000162 AC: 5 AN: 30862

American (AMR) AF: 0.0000948 AC: 1 AN: 10547

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3562

South Asian (SAS) AF: 0.00 AC: 0 AN: 2736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53251

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PDHA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0020
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs748635462; hg19: chrX-19378857;