rs10424582

chr19-29702814-G-Achr19-29702814-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031448.6(C19orf12):c.324C>T(p.Thr108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,613,648 control chromosomes in the GnomAD database, including 430,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39475 hom., cov: 31)
  • Exomes 𝑓: 0.73 (391083 hom.)
• Consequence: C19orf12 NM_031448.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.126

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-29702814-G-A is Benign according to our data. Variant chr19-29702814-G-A is described in ClinVar as [Benign]. Clinvar id is 128537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702814-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.126 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6	c.324C>T	p.Thr108=	synonymous_variant	3/3	ENST00000323670.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C19orf12	ENST00000323670.14	c.324C>T	p.Thr108=	synonymous_variant	3/3	2	NM_031448.6	P1

Frequencies

GnomAD3 genomes AF: 0.713 AC: 108254 AN: 151922 Hom.: 39453 Cov.: 31

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.731

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.752

Gnomad OTH AF: 0.698

GnomAD3 exomes AF: 0.655 AC: 164452 AN: 251040 Hom.: 56629 AF XY: 0.665 AC XY: 90329 AN XY: 135766

Gnomad AFR exome AF: 0.777

Gnomad AMR exome AF: 0.452

Gnomad ASJ exome AF: 0.737

Gnomad EAS exome AF: 0.302

Gnomad SAS exome AF: 0.645

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.752

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.725 AC: 1060037 AN: 1461608 Hom.: 391083 Cov.: 83 AF XY: 0.724 AC XY: 526598 AN XY: 727054

Gnomad4 AFR exome AF: 0.776

Gnomad4 AMR exome AF: 0.466

Gnomad4 ASJ exome AF: 0.735

Gnomad4 EAS exome AF: 0.308

Gnomad4 SAS exome AF: 0.648

Gnomad4 FIN exome AF: 0.661

Gnomad4 NFE exome AF: 0.759

Gnomad4 OTH exome AF: 0.712

GnomAD4 genome AF: 0.712 AC: 108319 AN: 152040 Hom.: 39475 Cov.: 31 AF XY: 0.699 AC XY: 51956 AN XY: 74324

Gnomad4 AFR AF: 0.775

Gnomad4 AMR AF: 0.574

Gnomad4 ASJ AF: 0.731

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.632

Gnomad4 FIN AF: 0.641

Gnomad4 NFE AF: 0.752

Gnomad4 OTH AF: 0.699

Alfa AF: 0.751 Hom.: 24240

Bravo AF: 0.708

Asia WGS AF: 0.510 AC: 1775 AN: 3478

EpiCase AF: 0.746

EpiControl AF: 0.746

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodegeneration with brain iron accumulation 4 Benign:5

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Mar 07, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

Hereditary spastic paraplegia 43 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.7
Dann	Benign	0.64

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: rs10424582; hg19: chr19-30193721; COSMIC: COSV60364385; COSMIC: COSV60364385;