19-29699249-C-T

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.*3463G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0981 in 450,000 control chromosomes in the GnomAD database, including 3,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (2486 hom., cov: 30)
  • Exomes 𝑓: 0.077 (1250 hom.)
• Consequence: C19orf12 NM_031448.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.42

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=-1.04).
• BP6: Variant 19-29699249-C-T is Benign according to our data. Variant chr19-29699249-C-T is described in ClinVar as [Benign]. Clinvar id is 328659.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6	c.*3463G>A		3_prime_UTR_variant	3/3	ENST00000323670.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C19orf12	ENST00000323670.14	c.*3463G>A		3_prime_UTR_variant	3/3	2	NM_031448.6	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21198 AN: 151492 Hom.: 2480 Cov.: 30

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0790

Gnomad ASJ AF: 0.0987

Gnomad EAS AF: 0.0349

Gnomad SAS AF: 0.0579

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0725

Gnomad OTH AF: 0.100

GnomAD3 exomes AF: 0.0781 AC: 9877 AN: 126400 Hom.: 657 AF XY: 0.0755 AC XY: 5224 AN XY: 69202

Gnomad AFR exome AF: 0.334

Gnomad AMR exome AF: 0.0499

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.0340

Gnomad SAS exome AF: 0.0641

Gnomad FIN exome AF: 0.0724

Gnomad NFE exome AF: 0.0726

Gnomad OTH exome AF: 0.0766

GnomAD4 exome AF: 0.0769 AC: 22932 AN: 298390 Hom.: 1250 Cov.: 0 AF XY: 0.0739 AC XY: 12551 AN XY: 169842

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.0497

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0324

Gnomad4 SAS exome AF: 0.0631

Gnomad4 FIN exome AF: 0.0702

Gnomad4 NFE exome AF: 0.0737

Gnomad4 OTH exome AF: 0.0866

GnomAD4 genome AF: 0.140 AC: 21223 AN: 151610 Hom.: 2486 Cov.: 30 AF XY: 0.135 AC XY: 10012 AN XY: 74038

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.0788

Gnomad4 ASJ AF: 0.0987

Gnomad4 EAS AF: 0.0346

Gnomad4 SAS AF: 0.0578

Gnomad4 FIN AF: 0.0715

Gnomad4 NFE AF: 0.0725

Gnomad4 OTH AF: 0.0987

Alfa AF: 0.0499 Hom.: 51

Bravo AF: 0.150

Asia WGS AF: 0.0790 AC: 274 AN: 3478

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 12, 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	1.4
Dann	Benign	0.57

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: rs150123154; hg19: chr19-30190156;