19-29699376-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031448.6(C19orf12):c.*3336C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 375,822 control chromosomes in the GnomAD database, including 677 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.059 (444 hom., cov: 30)
  • Exomes 𝑓: 0.036 (233 hom.)
• Consequence: C19orf12 NM_031448.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.02

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 19-29699376-G-A is Benign according to our data. Variant chr19-29699376-G-A is described in ClinVar as [Benign]. Clinvar id is 328665.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6	c.*3336C>T		3_prime_UTR_variant	3/3	ENST00000323670.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C19orf12	ENST00000323670.14	c.*3336C>T		3_prime_UTR_variant	3/3	2	NM_031448.6	P1

Frequencies

GnomAD3 genomes AF: 0.0588 AC: 8916 AN: 151548 Hom.: 441 Cov.: 30

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.0741

Gnomad EAS AF: 0.0822

Gnomad SAS AF: 0.0554

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0600

GnomAD3 exomes AF: 0.0458 AC: 3336 AN: 72770 Hom.: 120 AF XY: 0.0453 AC XY: 1827 AN XY: 40300

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0290

Gnomad ASJ exome AF: 0.0685

Gnomad EAS exome AF: 0.0777

Gnomad SAS exome AF: 0.0532

Gnomad FIN exome AF: 0.0225

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0382

GnomAD4 exome AF: 0.0359 AC: 8051 AN: 224160 Hom.: 233 Cov.: 0 AF XY: 0.0368 AC XY: 4717 AN XY: 128170

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0287

Gnomad4 ASJ exome AF: 0.0713

Gnomad4 EAS exome AF: 0.0788

Gnomad4 SAS exome AF: 0.0485

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.0244

Gnomad4 OTH exome AF: 0.0433

GnomAD4 genome AF: 0.0590 AC: 8945 AN: 151662 Hom.: 444 Cov.: 30 AF XY: 0.0586 AC XY: 4347 AN XY: 74120

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.0382

Gnomad4 ASJ AF: 0.0741

Gnomad4 EAS AF: 0.0824

Gnomad4 SAS AF: 0.0555

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0246

Gnomad4 OTH AF: 0.0636

Alfa AF: 0.0426 Hom.: 48

Bravo AF: 0.0621

Asia WGS AF: 0.0940 AC: 326 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration with brain iron accumulation 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.28
Dann	Benign	0.83

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: rs10414583; hg19: chr19-30190283;