19-29699141-G-A

Variant names:

• chr19-29699141-G-A
• rs74868577
• NM_031448.6:c.*3571C>T

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.*3571C>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 0.0044 in 453,778 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (30 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (14 hom.)
• Consequence: C19orf12 NM_031448.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.774

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=-0.93).
• BP6: Variant 19-29699141-G-A is Benign according to our data. Variant chr19-29699141-G-A is described in ClinVar as [Benign]. Clinvar id is 328655.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1521/151990) while in subpopulation AFR AF= 0.0347 (1439/41446). AF 95% confidence interval is 0.0332. There are 30 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C19orf12	NM_031448.6	c.*3571C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000323670.14	NP_113636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670	c.*3571C>T		3_prime_UTR_variant	Exon 3 of 3	2	NM_031448.6	ENSP00000313332.9

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1519 AN: 151874 Hom.: 30 Cov.: 31

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00394

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00529

GnomAD3 exomes AF: 0.00252 AC: 322 AN: 128030 Hom.: 9 AF XY: 0.00203 AC XY: 142 AN XY: 70116

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00157 AC: 475 AN: 301788 Hom.: 14 Cov.: 0 AF XY: 0.00124 AC XY: 213 AN XY: 171992

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.00299

GnomAD4 genome AF: 0.0100 AC: 1521 AN: 151990 Hom.: 30 Cov.: 31 AF XY: 0.00954 AC XY: 709 AN XY: 74306

Gnomad4 AFR AF: 0.0347

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00524

Alfa AF: 0.00910 Hom.: 5

Bravo AF: 0.0118

Asia WGS AF: 0.00202 AC: 7 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.93
CADD	Benign	1.1
DANN	Benign	0.38

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: rs74868577; hg19: chr19-30190048;