ENST00000544681.1:c.-279C>G

Variant names:

• chr12-6943843-C-G
• rs180837208
• ENST00000544681.1:c.-279C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BP4

The ENST00000544681.1(C12orf57):​c.-279C>G variant causes a 5 prime UTR 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 (★★). ClinVar reports functional evidence for this variant: "SCV002034789: 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)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: C12orf57 ENST00000544681.1 5_prime_UTR
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.71
• Publications: 2 publications found

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]

RNU7-1 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), PanelApp Australia

ENSG00000272173 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002034789: 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).; SCV005887048: "In functional studies the variant demonstrated impaired RNU7-1 function (Kolev_2006)."; SCV005333357: Published functional studies demonstrate severely impaired RNU7-1 function (PMID: 16547514)
• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000544681.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	NM_001301834.1		c.-16+181C>G		intron	N/A	NP_001288763.1	Q99622
	C12orf57	NM_001301836.2		c.13+181C>G		intron	N/A	NP_001288765.1
	RNU7-1	NR_023317.1		n.28C>G		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	ENST00000544681.1	TSL:2	c.-279C>G		5_prime_UTR	Exon 1 of 2	ENSP00000475422.1	U3KQ07
	C12orf57	ENST00000537087.5	TSL:2	c.-279C>G		5_prime_UTR	Exon 1 of 3	ENSP00000440937.1	F5GXW5
	C12orf57	ENST00000921170.1		c.-279C>G		5_prime_UTR	Exon 1 of 2	ENSP00000591229.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152210 Hom.: 0 Cov.: 33

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

African (AFR) AF: 0.000118 AC: 2 AN: 16936

American (AMR) AF: 0.0000621 AC: 1 AN: 16104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13394

East Asian (EAS) AF: 0.000120 AC: 3 AN: 24920

South Asian (SAS) AF: 0.000136 AC: 7 AN: 51292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19358

Middle Eastern (MID) AF: 0.000415 AC: 1 AN: 2412

European-Non Finnish (NFE) AF: 0.0000626 AC: 35 AN: 558886

Other (OTH) AF: 0.0000913 AC: 3 AN: 32842

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74492

African (AFR) AF: 0.0000481 AC: 2 AN: 41580

American (AMR) AF: 0.000196 AC: 3 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Aicardi-Goutieres syndrome 9 (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.88
PhyloP100		3.7
PromoterAI		-0.016	Neutral
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

Other links and lift over

dbSNP: rs180837208; hg19: chr12-7053006;