rs73023451

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

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. 14/21 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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.781

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM1

In a chain Protein C19orf12 (size 151) in uniprot entity CS012_HUMAN there are 29 pathogenic changes around while only 10 benign (74%) in NM_031448.6

BP4

Computational evidence support a benign effect (MetaRNN=0.006062269).

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 id is 380881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-29702725-T-C is described in Lovd as [Likely_benign]. Variant chr19-29702725-T-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C19orf12	NM_031448.6 linkuse as main transcript	c.413A>G	p.Gln138Arg	missense_variant	3/3	ENST00000323670.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C19orf12	ENST00000323670.14 linkuse as main transcript	c.413A>G	p.Gln138Arg	missense_variant	3/3	2	NM_031448.6	P1	Q9NSK7-4

Frequencies

GnomAD3 genomes

AF:

0.00255

AC:

388

AN:

152180

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00231

AC:

579

AN:

250284

Hom.:

AF XY:

0.00225

AC XY:

306

AN XY:

135744

show subpopulations

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 SAS exome

AF:

0.000261

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.:

Cov.:

AF XY:

0.00325

AC XY:

2362

AN XY:

727072

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00190

Gnomad4 NFE exome

AF:

0.00423

Gnomad4 OTH exome

AF:

0.00263

GnomAD4 genome

AF:

0.00254

AC:

387

AN:

152298

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00471

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00354

Hom.:

Bravo

AF:

0.00224

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00273

AC:

331

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00302

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	This variant is associated with the following publications: (PMID: 27112773) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	C19orf12: PP3, BS2 -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

- -

Hereditary spastic paraplegia 43

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Neurodegeneration with brain iron accumulation 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

Cadd

Benign

6.5

Dann

Benign

0.48

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.58

T;T;.;.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0061

T;T;T;T;T

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

N;N;N;N

Sift4G

Benign

0.53

T;T;T;T;T

Vest4

0.0060

MVP

0.21

MPC

0.37

ClinPred

0.0011

GERP RS

-4.1

Varity_R

0.027

gMVP

0.27

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over