12-6943845-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_001301834.1(C12orf57):​c.-16+183A>G variant causes a intron change. The variant allele was found at a frequency of 0.0000682 in 893,894 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 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

C12orf57
NM_001301834.1 intron

Scores

2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.38
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]
RNU7-1 (HGNC:34033): (RNA, U7 small nuclear 1) Implicated in Aicardi-Goutieres syndrome. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-6943845-A-G is Pathogenic according to our data. Variant chr12-6943845-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1328524.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.34). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
C12orf57NM_001301834.1 linkc.-16+183A>G intron_variant Intron 1 of 3 NP_001288763.1 Q99622
C12orf57NM_001301836.2 linkc.13+183A>G intron_variant Intron 1 of 2 NP_001288765.1
RNU7-1NR_023317.1 linkn.30A>G non_coding_transcript_exon_variant Exon 1 of 1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
C12orf57ENST00000544681 linkc.-277A>G 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 2 2 ENSP00000475422.1 U3KQ07
C12orf57ENST00000537087 linkc.-277A>G 5_prime_UTR_premature_start_codon_gain_variant Exon 1 of 3 2 ENSP00000440937.1 F5GXW5
C12orf57ENST00000544681 linkc.-277A>G 5_prime_UTR_variant Exon 1 of 2 2 ENSP00000475422.1 U3KQ07

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000742
AC:
55
AN:
741664
Hom.:
0
Cov.:
10
AF XY:
0.0000833
AC XY:
31
AN XY:
372056
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000120
Gnomad4 SAS exome
AF:
0.0000389
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000834
Gnomad4 OTH exome
AF:
0.0000303
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000416
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 9 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMay 26, 2021The RNU7-1 g.7053008A>G variant (chr12, hg19), also referred to as RNU7-1 (NR_023317.1) n.30A>G, is a non-coding transcript exon variant that has been reported in a four year old boy of European Russian descent with Aicardi-Goutieres syndrome in a compound heterozygous state with a second RNU7-1 variant, n.34_41del (Uggenti et al. 2020). The n.30A>G variant is reported at a frequency of 0.000065 in the European Non-Finnish population of the Genome Aggregation Database (version 2.1.1), an allele frequency consistent with a rare autosomal recessive disorder. The n.30A>G variant is located within the noncanonical Sm-binding site of U7 snRNA, a region which determines the assembly of the U7snRNP (Stefanovic et al. 1995). Using a chimeric mouse histone H4 pre-mRNA-U7 snRNA construct, in a xenopus oocyte in vitro system, Kolev et al. showed that substitution of alternative nucleotides at n.30A abolished pre-mRNA processing (Kolev et al. 2006). Based the evidence, the n.30A>G variant is classified as likely pathogenic for Aicardi-Goutieres syndrome. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.34
CADD
Benign
16
DANN
Benign
0.83

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.

Other links and lift over

dbSNP: rs781842057; hg19: chr12-7053008; API