rs146170087

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2

The NM_031448.6(C19orf12):ā€‹c.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

Scores

9
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:4B:8O:1

Conservation

PhyloP100: 1.51
Variant links:
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]

Genome browser will be placed here

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

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
C19orf12NM_031448.6 linkc.391A>G p.Lys131Glu missense_variant Exon 3 of 3 ENST00000323670.14 NP_113636.2 Q9NSK7-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
C19orf12ENST00000323670.14 linkc.391A>G p.Lys131Glu missense_variant Exon 3 of 3 2 NM_031448.6 ENSP00000313332.9 Q9NSK7-4

Frequencies

GnomAD3 genomes
AF:
0.00122
AC:
186
AN:
152142
Hom.:
3
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000982
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00973
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00153
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.00229
AC:
573
AN:
250744
Hom.:
3
AF XY:
0.00271
AC XY:
368
AN XY:
135794
show subpopulations
Gnomad AFR exome
AF:
0.000125
Gnomad AMR exome
AF:
0.000376
Gnomad ASJ exome
AF:
0.00259
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00964
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00195
Gnomad OTH exome
AF:
0.00229
GnomAD4 exome
AF:
0.00162
AC:
2367
AN:
1461672
Hom.:
15
Cov.:
30
AF XY:
0.00190
AC XY:
1379
AN XY:
727130
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.000537
Gnomad4 ASJ exome
AF:
0.00222
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00934
Gnomad4 FIN exome
AF:
0.0000940
Gnomad4 NFE exome
AF:
0.00120
Gnomad4 OTH exome
AF:
0.00180
GnomAD4 genome
AF:
0.00123
AC:
187
AN:
152260
Hom.:
3
Cov.:
32
AF XY:
0.00130
AC XY:
97
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.000241
Gnomad4 AMR
AF:
0.000981
Gnomad4 ASJ
AF:
0.00173
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00995
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00153
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00140
Hom.:
2
Bravo
AF:
0.00124
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00151
AC:
13
ExAC
AF:
0.00241
AC:
292
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00185
EpiControl
AF:
0.00196

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 providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 25, 2021This variant is associated with the following publications: (PMID: 30088953, 21981780, 25592411) -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023C19orf12: PM3, PM2:Supporting, BP4, BS2 -
Neurodegeneration with brain iron accumulation 4 Pathogenic:2Uncertain:2
Pathogenic, flagged submissionliterature onlyOMIMOct 07, 2011- -
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
Likely pathogenic, no assertion criteria providedprovider interpretationSolve-RD ConsortiumJun 01, 2022Variant confirmed as disease-causing by referring clinical team -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsDec 03, 2021- -
Hereditary spastic paraplegia 43 Benign:2
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2025- -
Likely benign, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness Pathogenic:1
Pathogenic, flagged submissionclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJul 01, 2015- -
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJan 31, 2017- -
Hereditary spastic paraplegia 5A Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesAug 07, 2018- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 11, 2023Variant 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 providedphenotyping onlyGenomeConnect, 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Uncertain
0.040
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.036
.;.;.;.;T
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.91
D;D;.;.;D
MetaRNN
Benign
0.0078
T;T;T;T;T
MetaSVM
Uncertain
-0.017
T
MutationAssessor
Uncertain
2.2
.;.;.;.;M
PROVEAN
Benign
-2.1
.;.;N;N;N
REVEL
Uncertain
0.55
Sift
Uncertain
0.019
.;.;D;D;T
Sift4G
Uncertain
0.017
D;T;T;D;T
Vest4
0.30
MVP
0.40
MPC
0.70
ClinPred
0.028
T
GERP RS
3.0
Varity_R
0.41
gMVP
0.47

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146170087; hg19: chr19-30193654; API