rs146170087

Variant names:

• chr19-29702747-T-C
• rs146170087
• NM_031448.6:c.391A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The ENST00000323670.14(C19orf12):​c.391A>G​(p.Lys131Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,932 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K131T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (15 hom.)
• Consequence: C19orf12 ENST00000323670.14 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:8 O:1
• Conservation: PhyloP100: 1.51
• Publications: 7 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: Benign. The variant received -12 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.007799536).
• BP6: Variant 19-29702747-T-C is Benign according to our data. Variant chr19-29702747-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 31158.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00123 (187/152260) while in subpopulation SAS AF = 0.00995 (48/4824). AF 95% confidence interval is 0.00771. There are 3 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,SD,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000323670.14. 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.391A>G	p.Lys131Glu	missense	Exon 3 of 3	NP_113636.2
	C19orf12	NM_001031726.4		c.391A>G	p.Lys131Glu	missense	Exon 3 of 3	NP_001026896.3
	C19orf12	NM_001256047.2		c.391A>G	p.Lys131Glu	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.391A>G	p.Lys131Glu	missense	Exon 3 of 3	ENSP00000313332.9
	C19orf12	ENST00000392276.1	TSL:1	c.199A>G	p.Lys67Glu	missense	Exon 2 of 2	ENSP00000376102.1
	C19orf12	ENST00000592153.5	TSL:1	c.*12A>G		3_prime_UTR	Exon 4 of 4	ENSP00000467117.1

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152142 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00229 AC: 573 AN: 250744 AF XY: 0.00271

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00259

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00162 AC: 2367 AN: 1461672 Hom.: 15 Cov.: 30 AF XY: 0.00190 AC XY: 1379 AN XY: 727130

African (AFR) AF: 0.000239 AC: 8 AN: 33478

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00934 AC: 806 AN: 86256

European-Finnish (FIN) AF: 0.0000940 AC: 5 AN: 53218

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5762

European-Non Finnish (NFE) AF: 0.00120 AC: 1339 AN: 1112004

Other (OTH) AF: 0.00180 AC: 109 AN: 60394

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152260 Hom.: 3 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74444

African (AFR) AF: 0.000241 AC: 10 AN: 41558

American (AMR) AF: 0.000981 AC: 15 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00995 AC: 48 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68012

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00143 Hom.: 9

Bravo AF: 0.00124

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00241 AC: 292

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
2	2	-	Neurodegeneration with brain iron accumulation 4 (4)
-	-	2	Hereditary spastic paraplegia 43 (2)
1	-	-	Dystonic disorder;C0040822:Tremor;C0234985:Mental deterioration;C0241688:Peripheral visual field loss;C4024790:Adult-onset night blindness (1)
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Hereditary spastic paraplegia 5A (1)
-	-	1	not specified (1)
-	-	-	Hereditary spastic paraplegia 43;C3280371:Neurodegeneration with brain iron accumulation 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.5
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.55
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.017	D
Vest4		0.30
MVP		0.40
MPC		0.70
ClinPred		0.028	T
GERP RS		3.0
Varity_R		0.41
gMVP		0.47
Mutation Taster		=86/14	disease causing (ClinVar)

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: rs146170087; hg19: chr19-30193654;