Genetic Variant NM_031448.6:c.313G>A (chr19-29702825-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_031448.6(C19orf12):c.313G>A(p.Val105Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,056 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. V105L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00094 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 6 hom. )

Consequence

C19orf12
NM_031448.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 1.49

Publications

2 publications found

Variant links:

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

C19orf12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.03429997).

BP6

Variant 19-29702825-C-T is Benign according to our data. Variant chr19-29702825-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286392.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000939 (143/152320) while in subpopulation NFE AF = 0.00172 (117/68010). AF 95% confidence interval is 0.00147. There are 1 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C19orf12	NM_031448.6	MANE Select	c.313G>A	p.Val105Met	missense	Exon 3 of 3	NP_113636.2	Q9NSK7-4
C19orf12	NM_001031726.4		c.313G>A	p.Val105Met	missense	Exon 3 of 3	NP_001026896.3	Q9NSK7-4
C19orf12	NM_001256047.2		c.313G>A	p.Val105Met	missense	Exon 3 of 3	NP_001242976.1	Q9NSK7-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C19orf12	ENST00000323670.14	TSL:2 MANE Select	c.313G>A	p.Val105Met	missense	Exon 3 of 3	ENSP00000313332.9	Q9NSK7-4
C19orf12	ENST00000591243.1	TSL:1	c.313G>A	p.Val105Met	missense	Exon 2 of 2	ENSP00000467516.1	K7EPS8
C19orf12	ENST00000392276.1	TSL:1	c.121G>A	p.Val41Met	missense	Exon 2 of 2	ENSP00000376102.1	Q9NSK7-2

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000972

AC:

244

AN:

251040

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00144

AC:

2103

AN:

1461736

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1055

AN XY:

727152

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00123

AC:

106

AN:

86256

European-Finnish (FIN)

AF:

0.000937

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00163

AC:

1817

AN:

1111942

Other (OTH)

AF:

0.00185

AC:

112

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

145

290

435

580

725

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000939

AC:

143

AN:

152320

Hom.:

Cov.:

AF XY:

0.000899

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41594

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00172

AC:

117

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00120

Hom.:

Bravo

AF:

0.000824

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000988

AC:

120

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hereditary spastic paraplegia (1)

Hereditary spastic paraplegia 43 (1)

Neurodegeneration with brain iron accumulation 4 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.034

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.2

PhyloP100

1.5

PROVEAN

Benign

-1.4

REVEL

Benign

0.24

Sift

Benign

0.090

Sift4G

Benign

0.11

Vest4

0.057

MVP

0.51

MPC

0.40

ClinPred

0.032

GERP RS

3.1

Varity_R

0.069

gMVP

0.64

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over