rs201118405

Variant names:

• chr19-29708345-C-T
• rs201118405
• NM_031448.6:c.69G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-29708345-C-T
• chr19-29708345-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031448.6(C19orf12):​c.69G>A​(p.Ala23Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,614,144 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (47 hom.)
• Consequence: C19orf12 NM_031448.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.70
• Publications: 4 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-29708345-C-T is Benign according to our data. Variant chr19-29708345-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.004 (610/152336) while in subpopulation NFE AF = 0.00723 (492/68032). AF 95% confidence interval is 0.0067. There are 3 homozygotes in GnomAd4. There are 272 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: 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.69G>A	p.Ala23Ala	synonymous	Exon 2 of 3	NP_113636.2	Q9NSK7-4
	C19orf12	NM_001031726.4		c.69G>A	p.Ala23Ala	synonymous	Exon 2 of 3	NP_001026896.3	Q9NSK7-4
	C19orf12	NM_001256047.2		c.69G>A	p.Ala23Ala	synonymous	Exon 2 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.69G>A	p.Ala23Ala	synonymous	Exon 2 of 3	ENSP00000313332.9	Q9NSK7-4
	C19orf12	ENST00000592153.5	TSL:1	c.69G>A	p.Ala23Ala	synonymous	Exon 2 of 4	ENSP00000467117.1	Q9NSK7-3
	C19orf12	ENST00000591243.1	TSL:1	c.69G>A	p.Ala23Ala	synonymous	Exon 1 of 2	ENSP00000467516.1	K7EPS8

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00723

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00360 AC: 899 AN: 249498 AF XY: 0.00385

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00652

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00658 AC: 9613 AN: 1461808 Hom.: 47 Cov.: 31 AF XY: 0.00636 AC XY: 4624 AN XY: 727204

African (AFR) AF: 0.00122 AC: 41 AN: 33480

American (AMR) AF: 0.00105 AC: 47 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00371 AC: 97 AN: 26136

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

South Asian (SAS) AF: 0.00112 AC: 97 AN: 86258

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53354

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.00803 AC: 8928 AN: 1111992

Other (OTH) AF: 0.00556 AC: 336 AN: 60396

GnomAD4 genome AF: 0.00400 AC: 610 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00365 AC XY: 272 AN XY: 74496

African (AFR) AF: 0.00164 AC: 68 AN: 41578

American (AMR) AF: 0.00177 AC: 27 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00723 AC: 492 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00535 Hom.: 1

Bravo AF: 0.00405

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00796

EpiControl AF: 0.00830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Neurodegeneration with brain iron accumulation 4 (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Hereditary spastic paraplegia 43 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.87
DANN	Benign	0.42
PhyloP100		-2.7
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=99/1	polymorphism

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: rs201118405; hg19: chr19-30199252; COSMIC: COSV100080595;