rs3763931

Variant names:

• chr11-34915869-G-A
• rs3763931
• NM_015957.4:c.57+359C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-34915869-G-A
• chr11-34915869-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015957.4(APIP):​c.57+359C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 328,206 control chromosomes in the GnomAD database, including 5,524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3904 hom., cov: 33)
  • Exomes 𝑓: 0.12 (1620 hom.)
• Consequence: APIP NM_015957.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.554
• Publications: 6 publications found

Genes affected

APIP (HGNC:17581): (APAF1 interacting protein) Enables identical protein binding activity; methylthioribulose 1-phosphate dehydratase activity; and zinc ion binding activity. Involved in several processes, including L-methionine salvage from methylthioadenosine; protein homotetramerization; and pyroptosis. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PDHX (HGNC:21350): (pyruvate dehydrogenase complex component X) The pyruvate dehydrogenase (PDH) complex is located in the mitochondrial matrix and catalyzes the conversion of pyruvate to acetyl coenzyme A. The PDH complex thereby links glycolysis to Krebs cycle. The PDH complex contains three catalytic subunits, E1, E2, and E3, two regulatory subunits, E1 kinase and E1 phosphatase, and a non-catalytic subunit, E3 binding protein (E3BP). This gene encodes the E3 binding protein subunit; also known as component X of the pyruvate dehydrogenase complex. This protein tethers E3 dimers to the E2 core of the PDH complex. Defects in this gene are a cause of pyruvate dehydrogenase deficiency which results in neurological dysfunction and lactic acidosis in infancy and early childhood. This protein is also a minor antigen for antimitochondrial antibodies. These autoantibodies are present in nearly 95% of patients with the autoimmune liver disease primary biliary cirrhosis (PBC). In PBC, activated T lymphocytes attack and destroy epithelial cells in the bile duct where this protein is abnormally distributed and overexpressed. PBC eventually leads to cirrhosis and liver failure. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Oct 2009]

PDHX Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• pyruvate dehydrogenase E3-binding protein deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 11-34915869-G-A is Benign according to our data. Variant chr11-34915869-G-A is described in ClinVar as Benign. ClinVar VariationId is 683419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015957.4. 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
	APIP	NM_015957.4	MANE Select	c.57+359C>T		intron	N/A	NP_057041.2	Q96GX9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APIP	ENST00000395787.4	TSL:1 MANE Select	c.57+359C>T		intron	N/A	ENSP00000379133.3	Q96GX9-1
	PDHX	ENST00000533550.5	TSL:4	c.-90G>A		5_prime_UTR	Exon 1 of 5	ENSP00000431281.1	E9PLU0
	APIP	ENST00000901543.1		c.57+359C>T		intron	N/A	ENSP00000571602.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28778 AN: 152060 Hom.: 3897 Cov.: 33

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0865

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.177

GnomAD4 exome AF: 0.120 AC: 21206 AN: 176028 Hom.: 1620 Cov.: 0 AF XY: 0.120 AC XY: 10827 AN XY: 90196

African (AFR) AF: 0.379 AC: 1814 AN: 4784

American (AMR) AF: 0.101 AC: 534 AN: 5302

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 945 AN: 6316

East Asian (EAS) AF: 0.0994 AC: 1249 AN: 12566

South Asian (SAS) AF: 0.120 AC: 1192 AN: 9916

European-Finnish (FIN) AF: 0.112 AC: 1412 AN: 12554

Middle Eastern (MID) AF: 0.146 AC: 137 AN: 936

European-Non Finnish (NFE) AF: 0.110 AC: 12367 AN: 112034

Other (OTH) AF: 0.134 AC: 1556 AN: 11620

GnomAD4 genome AF: 0.189 AC: 28819 AN: 152178 Hom.: 3904 Cov.: 33 AF XY: 0.186 AC XY: 13866 AN XY: 74420

African (AFR) AF: 0.391 AC: 16213 AN: 41490

American (AMR) AF: 0.110 AC: 1679 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 513 AN: 3470

East Asian (EAS) AF: 0.0867 AC: 449 AN: 5178

South Asian (SAS) AF: 0.114 AC: 550 AN: 4824

European-Finnish (FIN) AF: 0.117 AC: 1238 AN: 10608

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7734 AN: 67998

Other (OTH) AF: 0.175 AC: 370 AN: 2110

Alfa AF: 0.168 Hom.: 513

Bravo AF: 0.199

Asia WGS AF: 0.0890 AC: 308 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.64
DANN	Benign	0.93
PhyloP100		-0.55
PromoterAI		0.033	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3763931; hg19: chr11-34937416;