rs515726205

Positions:

• chr19-29702966-C-G
• chr19-29702966-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_031448.6(C19orf12):​c.172G>C​(p.Gly58Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G58S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C19orf12 NM_031448.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.26

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C19orf12	NM_031448.6	c.172G>C	p.Gly58Arg	missense_variant	3/3	ENST00000323670.14	NP_113636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14	c.172G>C	p.Gly58Arg	missense_variant	3/3	2	NM_031448.6	ENSP00000313332	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
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	0.56	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		0.71
MPC		1.1
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.86
gMVP		0.98

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

Other links and lift over

dbSNP: rs515726205; hg19: chr19-30193873;