rs146170087
Variant names:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2
The NM_031448.6(C19orf12):āc.391A>Gā(p.Lys131Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,932 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0012 ( 3 hom., cov: 32)
Exomes š: 0.0016 ( 15 hom. )
Consequence
C19orf12
NM_031448.6 missense
NM_031448.6 missense
Scores
9
8
Clinical Significance
Conservation
PhyloP100: 1.51
Genes affected
C19orf12 (HGNC:25443): (chromosome 19 open reading frame 12) This gene encodes a small transmembrane protein. Mutations in this gene are a cause of neurodegeneration with brain iron accumulation-4 (NBIA4), but the specific function of the encoded protein is unknown. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM1
In a chain Protein C19orf12 (size 151) in uniprot entity CS012_HUMAN there are 18 pathogenic changes around while only 7 benign (72%) in NM_031448.6
BP4
Computational evidence support a benign effect (MetaRNN=0.007799536).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00123 (187/152260) while in subpopulation SAS AF= 0.00995 (48/4824). AF 95% confidence interval is 0.00771. There are 3 homozygotes in gnomad4. There are 97 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd4 at 3 SD gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00122 AC: 186AN: 152142Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00229 AC: 573AN: 250744Hom.: 3 AF XY: 0.00271 AC XY: 368AN XY: 135794
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GnomAD4 exome AF: 0.00162 AC: 2367AN: 1461672Hom.: 15 Cov.: 30 AF XY: 0.00190 AC XY: 1379AN XY: 727130
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GnomAD4 genome AF: 0.00123 AC: 187AN: 152260Hom.: 3 Cov.: 32 AF XY: 0.00130 AC XY: 97AN XY: 74444
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:4Benign:8Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:5
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 25, 2021 | This variant is associated with the following publications: (PMID: 30088953, 21981780, 25592411) - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | C19orf12: PM3, PM2:Supporting, BP4, BS2 - |
Neurodegeneration with brain iron accumulation 4 Pathogenic:2Uncertain:2
Pathogenic, flagged submission | literature only | OMIM | Oct 07, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Likely pathogenic, no assertion criteria provided | provider interpretation | Solve-RD Consortium | Jun 01, 2022 | Variant confirmed as disease-causing by referring clinical team - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Dec 03, 2021 | - - |
Hereditary spastic paraplegia 43 Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2025 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness Pathogenic:1
Pathogenic, flagged submission | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jul 01, 2015 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 31, 2017 | - - |
Hereditary spastic paraplegia 5A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2023 | Variant summary: C19orf12 c.391A>G (p.Lys131Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 250744 control chromosomes, predominantly at a frequency of 0.0096 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in C19orf12 causing Neurodegeneration With Brain Iron Accumulation phenotype (0.0006), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments: benign (n=1), likely benign (n=3), uncertain significance (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. - |
Hereditary spastic paraplegia 43;C3280371:Neurodegeneration with brain iron accumulation 4 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;.;D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
.;.;.;.;M
PROVEAN
Benign
.;.;N;N;N
REVEL
Uncertain
Sift
Uncertain
.;.;D;D;T
Sift4G
Uncertain
D;T;T;D;T
Vest4
MVP
MPC
0.70
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at