NM_031448.6:c.*3304T>C

Variant names:

• chr19-29699408-A-G
• rs547761506
• NM_031448.6:c.*3304T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_031448.6(C19orf12):​c.*3304T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 387,416 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 30)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: C19orf12 NM_031448.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.06
• Publications: 0 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: AD, AR, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Illumina
• hereditary spastic paraplegia 43

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 19-29699408-A-G is Benign according to our data. Variant chr19-29699408-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 328666.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0036 (547/151794) while in subpopulation AFR AF = 0.0125 (517/41456). AF 95% confidence interval is 0.0116. There are 2 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,SD,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	NM_031448.6	MANE Select	c.*3304T>C		3_prime_UTR	Exon 3 of 3	NP_113636.2	Q9NSK7-4
	C19orf12	NM_001031726.4		c.*3304T>C		3_prime_UTR	Exon 3 of 3	NP_001026896.3	Q9NSK7-4
	C19orf12	NM_001256047.2		c.*3304T>C		3_prime_UTR	Exon 3 of 3	NP_001242976.1	Q9NSK7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.*3304T>C		3_prime_UTR	Exon 3 of 3	ENSP00000313332.9	Q9NSK7-4
	C19orf12	ENST00000890432.1		c.*3304T>C		3_prime_UTR	Exon 4 of 4	ENSP00000560491.1
	C19orf12	ENST00000623113.3	TSL:2	c.*3304T>C		downstream_gene	N/A	ENSP00000485413.2	Q9NSK7-4

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 544 AN: 151682 Hom.: 2 Cov.: 30

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

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: 0.0000294

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.000871 AC: 66 AN: 75806 AF XY: 0.000603

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.000678

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000410

GnomAD4 exome AF: 0.000352 AC: 83 AN: 235622 Hom.: 1 Cov.: 0 AF XY: 0.000253 AC XY: 34 AN XY: 134554

African (AFR) AF: 0.0106 AC: 60 AN: 5664

American (AMR) AF: 0.000682 AC: 9 AN: 13194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7218

East Asian (EAS) AF: 0.00 AC: 0 AN: 8542

South Asian (SAS) AF: 0.00 AC: 0 AN: 45774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 826

European-Non Finnish (NFE) AF: 0.00000750 AC: 1 AN: 133422

Other (OTH) AF: 0.00118 AC: 13 AN: 10986

GnomAD4 genome AF: 0.00360 AC: 547 AN: 151794 Hom.: 2 Cov.: 30 AF XY: 0.00349 AC XY: 259 AN XY: 74176

African (AFR) AF: 0.0125 AC: 517 AN: 41456

American (AMR) AF: 0.00145 AC: 22 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67956

Other (OTH) AF: 0.00285 AC: 6 AN: 2108

Alfa AF: 0.00231 Hom.: 0

Bravo AF: 0.00366

ClinVar

ClinVar submissions

Significance: Likely benign

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
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.79
DANN	Benign	0.12
PhyloP100		-2.1

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

Other links and lift over

dbSNP: rs547761506; hg19: chr19-30190315;