12-6943848-AGGCTTTCT-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NR_023317.1(RNU7-1):n.40_47del variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00014 in 899,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RNU7-1 NR_023317.1 non_coding_transcript_exon
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.70

Genes affected

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

(HGNC:):

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-6943848-AGGCTTTCT-A is Pathogenic according to our data. Variant chr12-6943848-AGGCTTTCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1202612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-6943848-AGGCTTTCT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNU7-1	NR_023317.1	n.40_47del		non_coding_transcript_exon_variant	1/1
C12orf57	NM_001301834.1	c.-16+193_-16+200del		intron_variant
C12orf57	NM_001301836.2	c.13+193_13+200del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNU7-1	ENST00000458811.1	n.40_47del		non_coding_transcript_exon_variant	1/1
	ENST00000607421.2	n.775_782del		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 101 AN: 746870 Hom.: 0 AF XY: 0.000141 AC XY: 53 AN XY: 374746

Gnomad4 AFR exome AF: 0.000234

Gnomad4 AMR exome AF: 0.0000610

Gnomad4 ASJ exome AF: 0.000147

Gnomad4 EAS exome AF: 0.0000389

Gnomad4 SAS exome AF: 0.000214

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000180

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74326

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000159

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	RNU7-1: PM3:Strong, PM2, PS3:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2023	This variant is associated with the following publications: (PMID: 35320431, 33230297, 37152446) -

Aicardi-Goutieres syndrome 9 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1255543147; hg19: chr12-7053011;