rs995720508

Variant names:

• chrX-19360955-G-A
• rs995720508
• NM_000284.4:c.*1302G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-19360955-G-A
• chrX-19360955-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000284.4(PDHA1):​c.*1302G>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 0.000144 in 501,598 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00014 (0 hom. 17 hem.)
• Consequence: PDHA1 NM_000284.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.391
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-19360955-G-A is Benign according to our data. Variant chrX-19360955-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2660125.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000159 (18/113182) while in subpopulation NFE AF = 0.000337 (18/53419). AF 95% confidence interval is 0.000218. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 XL,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000284.4. 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
	PDHA1	NM_000284.4	MANE Select	c.*1302G>A		3_prime_UTR	Exon 11 of 11	NP_000275.1	P08559-1
	MAP3K15	NM_001001671.4	MANE Select	c.3858-122C>T		intron	N/A	NP_001001671.3	Q6ZN16-1
	PDHA1	NM_001173454.2		c.*1302G>A		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
	PDHA1	ENST00000422285.7	TSL:1 MANE Select	c.*1302G>A		3_prime_UTR	Exon 11 of 11	ENSP00000394382.2	P08559-1
	MAP3K15	ENST00000338883.9	TSL:5 MANE Select	c.3858-122C>T		intron	N/A	ENSP00000345629.4	Q6ZN16-1
	PDHA1	ENST00000947567.1		c.*1302G>A		3_prime_UTR	Exon 13 of 13	ENSP00000617626.1

Frequencies

GnomAD3 genomes AF: 0.000159 AC: 18 AN: 113182 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000337

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000139 AC: 54 AN: 388416 Hom.: 0 Cov.: 6 AF XY: 0.000153 AC XY: 17 AN XY: 110924

African (AFR) AF: 0.0000899 AC: 1 AN: 11118

American (AMR) AF: 0.00 AC: 0 AN: 14554

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10360

East Asian (EAS) AF: 0.00 AC: 0 AN: 23711

South Asian (SAS) AF: 0.00 AC: 0 AN: 26506

European-Finnish (FIN) AF: 0.0000824 AC: 2 AN: 24259

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2353

European-Non Finnish (NFE) AF: 0.000201 AC: 51 AN: 253883

Other (OTH) AF: 0.00 AC: 0 AN: 21672

GnomAD4 genome AF: 0.000159 AC: 18 AN: 113182 Hom.: 0 Cov.: 24 AF XY: 0.000113 AC XY: 4 AN XY: 35320

African (AFR) AF: 0.00 AC: 0 AN: 31214

American (AMR) AF: 0.00 AC: 0 AN: 10744

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3623

South Asian (SAS) AF: 0.00 AC: 0 AN: 2794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6281

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.000337 AC: 18 AN: 53419

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.00113 Hom.: 4

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.41
DANN	Benign	0.73
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs995720508; hg19: chrX-19379073;