19-29699194-G-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.*3518C>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 0.077 in 453,732 control chromosomes in the GnomAD database, including 2,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.058 (393 hom., cov: 31)
  • Exomes 𝑓: 0.086 (1627 hom.)
• Consequence: C19orf12 NM_031448.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.359

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=-1.05).
• BP6: Variant 19-29699194-G-T is Benign according to our data. Variant chr19-29699194-G-T is described in ClinVar as [Benign]. Clinvar id is 328657.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6	c.*3518C>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.*3518C>A		3_prime_UTR_variant	3/3	2	NM_031448.6	P1

Frequencies

GnomAD3 genomes AF: 0.0582 AC: 8833 AN: 151880 Hom.: 393 Cov.: 31

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0176

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.0879

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0695

Gnomad OTH AF: 0.0503

GnomAD3 exomes AF: 0.0848 AC: 10850 AN: 127982 Hom.: 706 AF XY: 0.0931 AC XY: 6526 AN XY: 70090

Gnomad AFR exome AF: 0.00904

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.196

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.0886

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0637

GnomAD4 exome AF: 0.0865 AC: 26092 AN: 301734 Hom.: 1627 Cov.: 0 AF XY: 0.0966 AC XY: 16618 AN XY: 171964

Gnomad4 AFR exome AF: 0.00959

Gnomad4 AMR exome AF: 0.0282

Gnomad4 ASJ exome AF: 0.0405

Gnomad4 EAS exome AF: 0.197

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.0860

Gnomad4 NFE exome AF: 0.0665

Gnomad4 OTH exome AF: 0.0752

GnomAD4 genome AF: 0.0581 AC: 8830 AN: 151998 Hom.: 393 Cov.: 31 AF XY: 0.0620 AC XY: 4608 AN XY: 74292

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.0369

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.182

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.0879

Gnomad4 NFE AF: 0.0695

Gnomad4 OTH AF: 0.0545

Alfa AF: 0.0465 Hom.: 54

Bravo AF: 0.0482

Asia WGS AF: 0.178 AC: 617 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 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	-1.1
Cadd	Benign	0.35
Dann	Benign	0.39

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: rs62105838; hg19: chr19-30190101;