rs73023451

Variant names:

• chr19-29702725-T-C
• rs73023451
• NM_031448.6:c.413A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP2 PP3 BP6_Very_Strong BS1 BS2

The NM_031448.6(C19orf12):​c.413A>G​(p.Gln138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,613,840 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q138K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: C19orf12 NM_031448.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.781
• Publications: 8 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 -14 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 19-29702725-T-C is Benign according to our data. Variant chr19-29702725-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 380881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00254 (387/152298) while in subpopulation NFE AF = 0.00471 (320/68006). AF 95% confidence interval is 0.00428. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.413A>G	p.Gln138Arg	missense	Exon 3 of 3	NP_113636.2
	C19orf12	NM_001031726.4		c.413A>G	p.Gln138Arg	missense	Exon 3 of 3	NP_001026896.3
	C19orf12	NM_001256047.2		c.413A>G	p.Gln138Arg	missense	Exon 3 of 3	NP_001242976.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.413A>G	p.Gln138Arg	missense	Exon 3 of 3	ENSP00000313332.9
	C19orf12	ENST00000392276.1	TSL:1	c.221A>G	p.Gln74Arg	missense	Exon 2 of 2	ENSP00000376102.1
	C19orf12	ENST00000592153.5	TSL:1	c.*34A>G		3_prime_UTR	Exon 4 of 4	ENSP00000467117.1

Frequencies

GnomAD3 genomes AF: 0.00255 AC: 388 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00231 AC: 579 AN: 250284 AF XY: 0.00225

Gnomad AFR exome AF: 0.000573

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00344 AC: 5025 AN: 1461542 Hom.: 11 Cov.: 30 AF XY: 0.00325 AC XY: 2362 AN XY: 727072

African (AFR) AF: 0.000597 AC: 20 AN: 33478

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86250

European-Finnish (FIN) AF: 0.00190 AC: 101 AN: 53154

Middle Eastern (MID) AF: 0.000525 AC: 3 AN: 5712

European-Non Finnish (NFE) AF: 0.00423 AC: 4703 AN: 1112006

Other (OTH) AF: 0.00263 AC: 159 AN: 60384

GnomAD4 genome AF: 0.00254 AC: 387 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74474

African (AFR) AF: 0.000890 AC: 37 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00471 AC: 320 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00325 Hom.: 1

Bravo AF: 0.00224

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00273 AC: 331

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00302

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 43 (1)
-	-	1	Neurodegeneration with brain iron accumulation 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.5
DANN	Benign	0.48
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.10	N
PhyloP100		-0.78
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.10
Sift	Benign	0.63	T
Sift4G	Benign	0.53	T
Vest4		0.0060
MVP		0.21
MPC		0.37
ClinPred		0.0011	T
GERP RS		-4.1
Varity_R		0.027
gMVP		0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: 0

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

Other links and lift over

dbSNP: rs73023451; hg19: chr19-30193632;