Variant rs398122409 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_031448.6(C19orf12):c.164_166del(p.Gly55del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000178 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G55G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

C19orf12
NM_031448.6 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.37

Variant links:

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]

C19orf12 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity CS012_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_031448.6

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_031448.6. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 19-29702971-GCCC-G is Pathogenic according to our data. Variant chr19-29702971-GCCC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702971-GCCC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C19orf12	NM_031448.6 linkuse as main transcript	c.164_166del	p.Gly55del	inframe_deletion	3/3	ENST00000323670.14	NP_113636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14 linkuse as main transcript	c.164_166del	p.Gly55del	inframe_deletion	3/3	2	NM_031448.6	ENSP00000313332	P1	Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248898

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461810

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000264

AC:

AN:

151632

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74036

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 27, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate abnormal subcellular protein distribution (Landoure et al., 2013); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23857908, 22584950) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -

Neurodegeneration with brain iron accumulation 4

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 08, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2013	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Oct 23, 2023	The variant C19orf12:c.164_166delGGG, p.(Gly55del), which is located in the coding exon 3 of the C19orf12 gene, results from a three-base deletion at nucleotide position c.164_166. The glycine at protein position 55 is deleted. This amino acid position is located in a transmembrane domain of the protein and is evolutionarily highly conserved. The variant has been consistenly classified as Pathogenic or Likely pathogenic in seven entries in ClinVar (ClinVar ID: 88866). The variant has been described in compound heterozygosity with another pathogenic deletion (PMID: 22584950). Experimental studies showed a deleterious effect in the protein since the variant affected the proper subcellular localisation of the altered protein (PMID: 23857908). The variant is classified as rare in the overall population (allele frequency= 0.00001859 in gnomAD v4.1.0). In summary, this variant is classified as Likely pathogenic. -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 29, 2023

Variant summary: C19orf12 c.164_166delGGG/p.Gly55del (legacy name: c.197_199delGGG/p.Gly66del) results in an in-frame deletion that is predicted to remove one amino acid from the transmembrane domain of the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 248898 control chromosomes. c.164_166delGGG has been reported in the literature as a compound heterozygous genotype in at-least three individuals affected with Neurodegeneration With Brain Iron Accumulation (example, Deschauer_2012 cited in Dusek_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Neurofibromatosis, type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Oct 19, 2023

The variant C19orf12:c.164_166delGGG, p.(Gly55del), which is located in the coding exon 3 of the C19orf12 gene, results from a three-base deletion at nucleotide position c.164_166. The glycine at protein position 55 is deleted. This amino acid position is located in a transmembrane domain of the protein and is evolutionarily highly conserved. The variant has been consistenly classified as Pathogenic or Likely pathogenic in seven entries in ClinVar (ClinVar ID: 88866). The variant has been described in compound heterozygosity with another pathogenic deletion (PMID: 22584950). Experimental studies showed a deleterious effect in the protein since the variant affected the proper subcellular localisation of the altered protein (PMID: 23857908). The variant is classified as rare in the overall population (allele frequency= 0.00001859 in gnomAD v4.1.0). In summary, this variant is classified as Likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over