rs797045423

Variant names:

• chr19-29702912-TC-ACTGTTCCTCCA
• rs797045423
• NM_031448.6:c.225_226delGAinsTGGAGGAACAGT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1_Strong PM2 PP2 PP5_Moderate

The NM_031448.6(C19orf12):​c.225_226delGAinsTGGAGGAACAGT​(p.Gln75HisfsTer19) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C19orf12 NM_031448.6 frameshift, missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.65
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• neurodegeneration with brain iron accumulation 4

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Illumina, Ambry Genetics, G2P
• hereditary spastic paraplegia 43

  Inheritance: AR Classification: LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 1.0658 (below the threshold of 3.09). GenCC associations: The gene is linked to neurodegeneration with brain iron accumulation 4, hereditary spastic paraplegia 43.
• PP5: Variant 19-29702912-TC-ACTGTTCCTCCA is Pathogenic according to our data. Variant chr19-29702912-TC-ACTGTTCCTCCA is described in ClinVar as Pathogenic. ClinVar VariationId is 210552.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031448.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	NM_031448.6	MANE Select	c.225_226delGAinsTGGAGGAACAGT	p.Gln75HisfsTer19	frameshift missense	Exon 3 of 3	NP_113636.2
	C19orf12	NM_001031726.4		c.225_226delGAinsTGGAGGAACAGT	p.Gln75HisfsTer19	frameshift missense	Exon 3 of 3	NP_001026896.3
	C19orf12	NM_001256047.2		c.225_226delGAinsTGGAGGAACAGT	p.Gln75HisfsTer19	frameshift missense	Exon 3 of 3	NP_001242976.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.225_226delGAinsTGGAGGAACAGT	p.Gln75HisfsTer19	frameshift missense	Exon 3 of 3	ENSP00000313332.9
	C19orf12	ENST00000592153.5	TSL:1	c.225_226delGAinsTGGAGGAACAGT	p.Gln75HisfsTer19	frameshift missense	Exon 3 of 4	ENSP00000467117.1
	C19orf12	ENST00000591243.1	TSL:1	c.225_226delGAinsTGGAGGAACAGT	p.Gln75HisfsTer19	frameshift missense	Exon 2 of 2	ENSP00000467516.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodegeneration with brain iron accumulation 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045423; hg19: chr19-30193819;