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12-6943843-C-G

Variant summary

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

The NR_023317.1(RNU7-1):n.28C>G variant causes a non coding transcript exon 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

RNU7-1
NR_023317.1 non_coding_transcript_exon

Scores

2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.71
Variant links:
Genes affected
RNU7-1 (HGNC:34033): (RNA, U7 small nuclear 1) Implicated in Aicardi-Goutieres syndrome. [provided by Alliance of Genome Resources, Apr 2022]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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_single_submitter, 1 stars.
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
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/exons MANE UniProt
RNU7-1NR_023317.1 linkuse as main transcriptn.28C>G non_coding_transcript_exon_variant 1/1
C12orf57NM_001301834.1 linkuse as main transcriptc.-16+181C>G intron_variant
C12orf57NM_001301836.2 linkuse as main transcriptc.13+181C>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RNU7-1ENST00000458811.1 linkuse as main transcriptn.28C>G non_coding_transcript_exon_variant 1/1
ENST00000607421.2 linkuse as main transcriptn.788G>C non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000591
AC:
9
AN:
152210
Hom.:
0
Cov.:
33
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:
52
AN:
736144
Hom.:
0
Cov.:
10
AF XY:
0.0000785
AC XY:
29
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000591
AC:
9
AN:
152328
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
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: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, IlluminaJul 28, 2021The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.22
Cadd
Benign
17
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.

Other links and lift over

dbSNP: rs180837208; hg19: chr12-7053006; API