Variant 12-6943845-A-G details in Genebe, Genetics Data Aggregator

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

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]

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:

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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	Effect	Exon rank	Protein	UniProt
C12orf57	NM_001301834.1 link	c.-16+183A>G	intron_variant	Intron 1 of 3	NP_001288763.1	Q99622
C12orf57	NM_001301836.2 link	c.13+183A>G	intron_variant	Intron 1 of 2	NP_001288765.1
RNU7-1	NR_023317.1 link	n.30A>G	non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
C12orf57	ENST00000544681 link	c.-277A>G	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	2	ENSP00000475422.1	U3KQ07
C12orf57	ENST00000537087 link	c.-277A>G	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	2	ENSP00000440937.1	F5GXW5
C12orf57	ENST00000544681 link	c.-277A>G	5_prime_UTR_variant	Exon 1 of 2	2	ENSP00000475422.1	U3KQ07

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152230

Hom.:

Cov.:

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:

AN:

741664

Hom.:

Cov.:

AF XY:

0.0000833

AC XY:

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:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

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:

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

May 26, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

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.

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