NM_031448.6:c.164_166delGGG

Variant names:

• chr19-29702971-GCCC-G
• rs398122409
• NM_031448.6:c.164_166delGGG

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_031448.6(C19orf12):​c.164_166delGGG​(p.Gly55del) variant causes a disruptive 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 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 4.37

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 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 rank	MANE	Protein	UniProt
C19orf12	NM_031448.6	c.164_166delGGG	p.Gly55del	disruptive_inframe_deletion	Exon 3 of 3	ENST00000323670.14	NP_113636.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C19orf12	ENST00000323670.14	c.164_166delGGG	p.Gly55del	disruptive_inframe_deletion	Exon 3 of 3	2	NM_031448.6	ENSP00000313332.9

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151632 Hom.: 0 Cov.: 32

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: 3 AN: 248898 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134812

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: 26 AN: 1461810 Hom.: 0 AF XY: 0.0000151 AC XY: 11 AN XY: 727212

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: 4 AN: 151632 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74036

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Jan 27, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neurodegeneration with brain iron accumulation 4 Pathogenic:3

Oct 23, 2023

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Nov 08, 2022

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neurodegeneration with brain iron accumulation Pathogenic:1

Mar 29, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary spastic paraplegia 43;C3280371:Neurodegeneration with brain iron accumulation 4 Pathogenic:1

Mar 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurofibromatosis, type 1 Pathogenic:1

Oct 19, 2023

Diagnostics Centre, Carl Von Ossietzky University Oldenburg

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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: rs398122409; hg19: chr19-30193878;