Genetic Variant C12orf57:c.-279C>G (chr12-6943843-C-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001301834.1(C12orf57):c.-16+181C>G variant causes a intron change. The variant allele was found at a frequency of 0.0000687 in 888,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

C12orf57
NM_001301834.1 intron

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 3.71

Variant links:

Genes affected

C12orf57 (HGNC:29521): (chromosome 12 open reading frame 57) This gene is ubiquitously expressed in human tissues. It is required for development of the human corpus callosum. Mutations in this gene are associated with Temtamy syndrome (TEMTYS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2014]

C12orf57 links:

RNU7-1 (HGNC:34033): (RNA, U7 small nuclear 1) Implicated in Aicardi-Goutieres syndrome. [provided by Alliance of Genome Resources, Apr 2022]

RNU7-1 links:

ENSG00000272173 (HGNC:):

ENSG00000272173 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-6943843-C-G is Pathogenic according to our data. Variant chr12-6943843-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1328141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.22). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf57	NM_138425.4 link	c.-279C>G		upstream_gene_variant		ENST00000229281.6	NP_612434.1	Q99622

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf57	ENST00000229281.6 link	c.-279C>G		upstream_gene_variant		1	NM_138425.4	ENSP00000229281.5		Q99622

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000706

AC:

AN:

736144

Hom.:

Cov.:

AF XY:

0.0000785

AC XY:

AN XY:

369454

show subpopulations

Gnomad4 AFR exome

AF:

0.000118

Gnomad4 AMR exome

AF:

0.0000621

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000120

Gnomad4 SAS exome

AF:

0.000136

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000626

Gnomad4 OTH exome

AF:

0.0000913

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 9

Pathogenic:2

Jul 28, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RNU7-1 n.28C>G variant is a non-protein coding variant that has not been reported in the peer-reviewed literature. However, a different nucleotide change at the same position, n.28C>T, has been reported in at least six individuals with Aicardi-Goutieres syndrome and elevated levels of interferon (Uggenti et al. 2020); in two of these individuals, the n.28C>T variant was confirmed in trans with the n.40_47del variant. The n.28C>G variant is reported at a frequency of 0.000196 in the Latino/Admixed American population of the Genome Aggregation Database (version 3.1.1), a frequency that is consistent with a rare autosomal recessive disorder. Nucleotide 28 is a key position of the sm-binding site, and functional studies have shown that the n.28C>G nucleotide substitution inhibits the assembly and processing efficiency of the U7 snRNP (Kolev and Steiz 2006). Based on the evidence, the n.28C>G variant is classified as likely pathogenic for Aicardi-Goutieres syndrome. -

Jan 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RNU7-1 n.28C>G alters a nucleotide in the non-coding RNA. The variant allele was found at a frequency of 6.9e-05 in 888472 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RNU7-1 causing Aicardi-Goutieres syndrome 9 (6.9e-05 vs 0.0011), allowing no conclusion about variant significance. n.28C>G has been reported in the literature in at least one individual affected with Aicardi-Goutieres syndrome (example: Louise Frmond_2023). In functional studies the variant demonstrated impaired RNU7-1 function (Kolev_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16547514, 37171742). ClinVar contains an entry for this variant (Variation ID: 1328141). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:2

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RNU7-1: PM3:Strong, PM2, PS1:Supporting -

Jan 29, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second RNU7-1 variant in a patient with nystagmus, microcephaly, and dystonia, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 37171742); Published functional studies demonstrate severely impaired RNU7-1 function (PMID: 16547514); Also known as n.28C>G; This variant is associated with the following publications: (PMID: 16547514, 33230297, 37171742) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Benign

0.88

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

Splicing

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