rs387907173

Variant names:

• chr19-29702776-A-G
• rs387907173
• NM_031448.6:c.362T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-29702776-A-G
• chr19-29702776-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM2 PM5 PP2 PP3 BP4

The ENST00000323670.14(C19orf12):​c.362T>C​(p.Leu121Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. L121Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: C19orf12 ENST00000323670.14 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.83
• 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-29702776-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 31626.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.35039353).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323670.14. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	NM_031448.6	MANE Select	c.362T>C	p.Leu121Pro	missense	Exon 3 of 3	NP_113636.2
	C19orf12	NM_001031726.4		c.362T>C	p.Leu121Pro	missense	Exon 3 of 3	NP_001026896.3
	C19orf12	NM_001256047.2		c.362T>C	p.Leu121Pro	missense	Exon 3 of 3	NP_001242976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.362T>C	p.Leu121Pro	missense	Exon 3 of 3	ENSP00000313332.9
	C19orf12	ENST00000592153.5	TSL:1	c.307T>C	p.Cys103Arg	missense	Exon 4 of 4	ENSP00000467117.1
	C19orf12	ENST00000392276.1	TSL:1	c.170T>C	p.Leu57Pro	missense	Exon 2 of 2	ENSP00000376102.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461622 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.49	D
PhyloP100		8.8
Sift4G	Benign	0.17	T
Vest4		0.20
MVP		0.62
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.91
Mutation Taster		=19/81	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

Other links and lift over

dbSNP: rs387907173; hg19: chr19-30193683;