19-29708345-C-A

Variant names:

• chr19-29708345-C-A
• NM_031448.6:c.69G>T
• C19orf12 p.Ala23Ala

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001282931.3(C19orf12):​c.-245G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C19orf12 NM_001282931.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.70
• 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, AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, ClinGen, G2P, Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 43

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282931.3. 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.69G>T	p.Ala23Ala	synonymous	Exon 2 of 3	NP_113636.2	Q9NSK7-4
	C19orf12	NM_001282931.3		c.-245G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001269860.1	Q9NSK7-2
	C19orf12	NM_001031726.4		c.69G>T	p.Ala23Ala	synonymous	Exon 2 of 3	NP_001026896.3	Q9NSK7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.69G>T	p.Ala23Ala	synonymous	Exon 2 of 3	ENSP00000313332.9	Q9NSK7-4
	C19orf12	ENST00000592153.5	TSL:1	c.69G>T	p.Ala23Ala	synonymous	Exon 2 of 4	ENSP00000467117.1	Q9NSK7-3
	C19orf12	ENST00000591243.1	TSL:1	c.69G>T	p.Ala23Ala	synonymous	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
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.17
DANN	Benign	0.39
PhyloP100		-2.7
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6

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: chr19-30199252;