chr19-29702966-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_031448.6(C19orf12):​c.172G>A​(p.Gly58Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G58S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

10
6
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.26
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 Pathogenic. Variant got 16 ACMG points.

PM1
In a transmembrane_region Helical (size 20) in uniprot entity CS012_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_031448.6
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.851
PP5
Variant 19-29702966-C-T is Pathogenic according to our data. Variant chr19-29702966-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
C19orf12NM_031448.6 linkuse as main transcriptc.172G>A p.Gly58Arg missense_variant 3/3 ENST00000323670.14 NP_113636.2 Q9NSK7-4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
C19orf12ENST00000323670.14 linkuse as main transcriptc.172G>A p.Gly58Arg missense_variant 3/32 NM_031448.6 ENSP00000313332.9 Q9NSK7-4

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000241
AC:
6
AN:
249134
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
134862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000538
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461626
Hom.:
0
Cov.:
37
AF XY:
0.0000151
AC XY:
11
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152082
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74288
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000445
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurodegeneration with brain iron accumulation 4 Pathogenic:4
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 05, 2018The p.Gly69Arg in C19orf12 has been reported in the homozygous or compound heter ozygous state in 6 individuals with mitochondrial membrane protein-associated ne urodegeneration (MPAN; Hartig 2011, Hogarth 2013, Goldman 2013, Tschentscher 201 5). It has also been identified in 7/124358 of European chromosomes by gnomAD (h ttp://gnomad.broadinstitute.org); however, this frequency is low enough to be co nsistent with a recessive carrier frequency. This variant has been reported in C linVar (Variation ID 183298). In vitro functional studies support an impact to p rotein function (Landoure 2013) and computational prediction tools and conservat ion analysis are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive MPA N. ACMG/AMP criteria applied: PM3_Strong, PM2, PP3, PS3_Supporting -
Pathogenic, no assertion criteria providedclinical testingAziz Sancar Institute of Experimental Medicine, Istanbul UniversityAug 08, 2018The c.205G>A; p.Gly69Arg (NM_001031726.3) variant is associated with neurodegeneration with brain iron accumulation (Hartig 2011). Our patient had slowly progressive spastic paraparesis without extrapyramidal signs. -
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 07, 2011- -
Likely pathogenic, criteria provided, single submitterclinical testingLaboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert EinsteinMay 07, 2021ACMG classification criteria: PS4 moderate, PM2, PM3, PP3 -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023C19orf12: PM3:Very Strong, PM2, PP3 -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityDec 12, 2019- -
Neurodegeneration with brain iron accumulation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 13, 2023Variant summary: C19orf12 c.172G>A (p.Gly58Arg), also referred to as c.205G>A (p.Gly69Arg), results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249134 control chromosomes (gnomAD). c.172G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation (e.g. Hartig_2011, Hogarth_2013, Tschentscher_2015). These data indicate that the variant is very likely to be associated with disease. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Hereditary spastic paraplegia 43 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 07, 2022For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects C19orf12 function (PMID: 23857908). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 31157). This missense change has been observed in individual(s) with neurodegeneration with brain iron accumulation (NBIA) (PMID: 21981780, 23269600, 23494994, 25592411, 30088953). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs515726205, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 69 of the C19orf12 protein (p.Gly69Arg). -
Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaJul 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
.;.;.;T;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;.;D;D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Pathogenic
2.9
.;.;.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PROVEAN
Pathogenic
-7.0
.;D;.;D;.
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0020
.;D;.;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;.
Vest4
0.94
MutPred
0.58
Gain of methylation at G58 (P = 0.0172);Gain of methylation at G58 (P = 0.0172);Gain of methylation at G58 (P = 0.0172);.;Gain of methylation at G58 (P = 0.0172);
MVP
0.73
MPC
1.1
ClinPred
0.97
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.86
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs515726205; hg19: chr19-30193873; COSMIC: COSV100080664; API