11-66848963-C-T

Position:

• chr11-66848963-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001040716.2(PC):​c.3473G>A​(p.Arg1158His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: PC NM_001040716.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.766

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PC. . Gene score misZ 3.0552 (greater than the threshold 3.09). Trascript score misZ 3.7621 (greater than threshold 3.09). GenCC has associacion of gene with pyruvate carboxylase deficiency, benign type, pyruvate carboxylase deficiency, severe neonatal type, pyruvate carboxylase deficiency, infantile form, pyruvate carboxylase deficiency disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15953273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PC	NM_001040716.2	c.3473G>A	p.Arg1158His	missense_variant	23/23	ENST00000393960.7	NP_001035806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PC	ENST00000393960.7	c.3473G>A	p.Arg1158His	missense_variant	23/23	5	NM_001040716.2	ENSP00000377532.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251206 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135830

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000226 AC: 331 AN: 1461704 Hom.: 0 Cov.: 32 AF XY: 0.000208 AC XY: 151 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74366

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000280 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyruvate carboxylase deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 21, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2021	This sequence change replaces arginine with histidine at codon 1158 of the PC protein (p.Arg1158His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs149054698, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with PC-related conditions. ClinVar contains an entry for this variant (Variation ID: 305615). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.035	T;T;T;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.0082
FATHMM_MKL	Benign	0.52	D
LIST_S2	Pathogenic	0.98	.;.;.;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.93	.;L;L;L
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Benign	0.069
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D
Polyphen		0.69	.;P;P;P
Vest4		0.038
MVP		0.45
MPC		0.62
ClinPred		0.095	T
GERP RS		1.8
Varity_R		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs149054698; hg19: chr11-66616434; COSMIC: COSV58994114; COSMIC: COSV58994114;