19-29699340-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_031448.6(C19orf12):c.*3372C>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 0.0115 in 365,318 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 30)
  • Exomes 𝑓: 0.012 (28 hom.)
• Consequence: C19orf12 NM_031448.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.364

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 19-29699340-G-A is Benign according to our data. Variant chr19-29699340-G-A is described in ClinVar as [Benign]. Clinvar id is 328663.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0105 (1593/151802) while in subpopulation NFE AF= 0.0172 (1168/67914). AF 95% confidence interval is 0.0164. There are 13 homozygotes in gnomad4. There are 716 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6	c.*3372C>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.*3372C>T		3_prime_UTR_variant	3/3	2	NM_031448.6	P1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1595 AN: 151684 Hom.: 13 Cov.: 30

Gnomad AFR AF: 0.00341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.00782

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0106 AC: 693 AN: 65640 Hom.: 4 AF XY: 0.0107 AC XY: 386 AN XY: 36022

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.00974

Gnomad ASJ exome AF: 0.00728

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00204

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0122 AC: 2600 AN: 213516 Hom.: 28 Cov.: 0 AF XY: 0.0113 AC XY: 1385 AN XY: 122160

Gnomad4 AFR exome AF: 0.00418

Gnomad4 AMR exome AF: 0.00898

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.0117

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0105 AC: 1593 AN: 151802 Hom.: 13 Cov.: 30 AF XY: 0.00965 AC XY: 716 AN XY: 74188

Gnomad4 AFR AF: 0.00340

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00168

Gnomad4 FIN AF: 0.00782

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0124 Hom.: 2

Bravo AF: 0.0105

Asia WGS AF: 0.00173 AC: 6 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	-1.0
Cadd	Benign	0.094
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117537955; hg19: chr19-30190247;