NM_031448.6:c.124G>C

Variant names:

• chr19-29708290-C-G
• NM_031448.6:c.124G>C
• C19orf12 p.Gly42Arg

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_Moderate PM1 PM2 PP2 PP3_Strong

The NM_031448.6(C19orf12):​c.124G>C​(p.Gly42Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C19orf12 NM_031448.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.08
• Publications: 0 publications found

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: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina
• hereditary spastic paraplegia 43

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS1: Transcript NM_031448.6 (C19orf12) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_031448.6
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.943

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031448.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	NM_031448.6	MANE Select	c.124G>C	p.Gly42Arg	missense	Exon 2 of 3	NP_113636.2	Q9NSK7-4
	C19orf12	NM_001031726.4		c.124G>C	p.Gly42Arg	missense	Exon 2 of 3	NP_001026896.3	Q9NSK7-4
	C19orf12	NM_001256047.2		c.124G>C	p.Gly42Arg	missense	Exon 2 of 3	NP_001242976.1	Q9NSK7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.124G>C	p.Gly42Arg	missense	Exon 2 of 3	ENSP00000313332.9	Q9NSK7-4
	C19orf12	ENST00000592153.5	TSL:1	c.124G>C	p.Gly42Arg	missense	Exon 2 of 4	ENSP00000467117.1	Q9NSK7-3
	C19orf12	ENST00000591243.1	TSL:1	c.124G>C	p.Gly42Arg	missense	Exon 1 of 2	ENSP00000467516.1	K7EPS8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.1
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
PromoterAI		0.018	Neutral
Varity_R		0.73
gMVP		0.99
Mutation Taster		=7/93	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-30199197;