11-66848793-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001040716.2(PC):c.*106G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0207 in 1,445,912 control chromosomes in the GnomAD database, including 538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (78 hom., cov: 33)
  • Exomes 𝑓: 0.021 (460 hom.)
• Consequence: PC NM_001040716.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.107

Genes affected

PC (HGNC:8636): (pyruvate carboxylase) This gene encodes pyruvate carboxylase, which requires biotin and ATP to catalyse the carboxylation of pyruvate to oxaloacetate. The active enzyme is a homotetramer arranged in a tetrahedron which is located exclusively in the mitochondrial matrix. Pyruvate carboxylase is involved in gluconeogenesis, lipogenesis, insulin secretion and synthesis of the neurotransmitter glutamate. Mutations in this gene have been associated with pyruvate carboxylase deficiency. Alternatively spliced transcript variants with different 5' UTRs, but encoding the same protein, have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-66848793-C-A is Benign according to our data. Variant chr11-66848793-C-A is described in ClinVar as [Benign]. Clinvar id is 877797.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0196 (2983/152356) while in subpopulation NFE AF= 0.0242 (1645/68020). AF 95% confidence interval is 0.0232. There are 78 homozygotes in gnomad4. There are 1669 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 78 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PC	NM_001040716.2	c.*106G>T		3_prime_UTR_variant	23/23	ENST00000393960.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PC	ENST00000393960.7	c.*106G>T		3_prime_UTR_variant	23/23	5	NM_001040716.2	P1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2983 AN: 152238 Hom.: 78 Cov.: 33

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0242

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.0208 AC: 26953 AN: 1293556 Hom.: 460 Cov.: 19 AF XY: 0.0206 AC XY: 13375 AN XY: 650542

Gnomad4 AFR exome AF: 0.00231

Gnomad4 AMR exome AF: 0.00765

Gnomad4 ASJ exome AF: 0.0106

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00513

Gnomad4 FIN exome AF: 0.0808

Gnomad4 NFE exome AF: 0.0219

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0196 AC: 2983 AN: 152356 Hom.: 78 Cov.: 33 AF XY: 0.0224 AC XY: 1669 AN XY: 74496

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.0843

Gnomad4 NFE AF: 0.0242

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0151 Hom.: 10

Bravo AF: 0.0131

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyruvate carboxylase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	1.9
Dann	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs45505701; hg19: chr11-66616264;