NM_031448.6:c.413A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PM1PP2PP3BP6_Very_StrongBS1BS2

The NM_031448.6(C19orf12):​c.413A>G​(p.Gln138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,613,840 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q138K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0034 ( 11 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

18

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.781

Publications

8 publications found
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]
C19orf12 Gene-Disease associations (from GenCC):
  • neurodegeneration with brain iron accumulation 4
    Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Illumina, Ambry Genetics, G2P
  • hereditary spastic paraplegia 43
    Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PM1
In a chain Protein C19orf12 (size 151) in uniprot entity CS012_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_031448.6
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 1.0658 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodegeneration with brain iron accumulation 4, hereditary spastic paraplegia 43.
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
Variant 19-29702725-T-C is Benign according to our data. Variant chr19-29702725-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 380881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00254 (387/152298) while in subpopulation NFE AF = 0.00471 (320/68006). AF 95% confidence interval is 0.00428. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR,SD,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
C19orf12NM_031448.6 linkc.413A>G p.Gln138Arg 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.413A>G p.Gln138Arg missense_variant Exon 3 of 3 2 NM_031448.6 ENSP00000313332.9 Q9NSK7-4

Frequencies

GnomAD3 genomes
AF:
0.00255
AC:
388
AN:
152180
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000893
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00132
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00472
Gnomad OTH
AF:
0.00144
GnomAD2 exomes
AF:
0.00231
AC:
579
AN:
250284
AF XY:
0.00225
show subpopulations
Gnomad AFR exome
AF:
0.000573
Gnomad AMR exome
AF:
0.000434
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00120
Gnomad NFE exome
AF:
0.00449
Gnomad OTH exome
AF:
0.00197
GnomAD4 exome
AF:
0.00344
AC:
5025
AN:
1461542
Hom.:
11
Cov.:
30
AF XY:
0.00325
AC XY:
2362
AN XY:
727072
show subpopulations
African (AFR)
AF:
0.000597
AC:
20
AN:
33478
American (AMR)
AF:
0.000425
AC:
19
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0000765
AC:
2
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.000209
AC:
18
AN:
86250
European-Finnish (FIN)
AF:
0.00190
AC:
101
AN:
53154
Middle Eastern (MID)
AF:
0.000525
AC:
3
AN:
5712
European-Non Finnish (NFE)
AF:
0.00423
AC:
4703
AN:
1112006
Other (OTH)
AF:
0.00263
AC:
159
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
335
670
1006
1341
1676
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
184
368
552
736
920
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00254
AC:
387
AN:
152298
Hom.:
2
Cov.:
32
AF XY:
0.00199
AC XY:
148
AN XY:
74474
show subpopulations
African (AFR)
AF:
0.000890
AC:
37
AN:
41572
American (AMR)
AF:
0.000588
AC:
9
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.000414
AC:
2
AN:
4828
European-Finnish (FIN)
AF:
0.00132
AC:
14
AN:
10624
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00471
AC:
320
AN:
68006
Other (OTH)
AF:
0.00142
AC:
3
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
22
45
67
90
112
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00325
Hom.:
1
Bravo
AF:
0.00224
TwinsUK
AF:
0.00405
AC:
15
ALSPAC
AF:
0.00441
AC:
17
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00349
AC:
30
ExAC
AF:
0.00273
AC:
331
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00316
EpiControl
AF:
0.00302

ClinVar

Significance: Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jan 13, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27112773) -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

May 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

C19orf12: PP3, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:1
-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Hereditary spastic paraplegia 43 Benign:1
Jan 27, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Neurodegeneration with brain iron accumulation 4 Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary spastic paraplegia Benign:1
Aug 24, 2020
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
6.5
DANN
Benign
0.48
DEOGEN2
Benign
0.0075
.;.;.;.;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.044
N
LIST_S2
Benign
0.58
T;T;.;.;T
M_CAP
Benign
0.070
D
MetaRNN
Benign
0.0061
T;T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.10
.;.;.;.;N
PhyloP100
-0.78
PROVEAN
Benign
-0.080
.;.;N;N;N
REVEL
Benign
0.10
Sift
Benign
0.63
.;.;T;T;T
Sift4G
Benign
0.53
T;T;T;T;T
Vest4
0.0060
MVP
0.21
MPC
0.37
ClinPred
0.0011
T
GERP RS
-4.1
Varity_R
0.027
gMVP
0.27
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.69
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.69
Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs73023451; hg19: chr19-30193632; API