NM_001301834.1:c.-16+1G>A

Variant names:

• chr12-6943663-G-A
• rs868972460
• NM_001301834.1:c.-16+1G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1 PM2 BS1_Supporting

The NM_001301834.1(C12orf57):​c.-16+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000699 in 1,287,962 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 Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: C12orf57 NM_001301834.1 splice_donor, intron
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.249

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]

ENSG00000272173 (HGNC:):

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000361 (41/1135690) while in subpopulation AFR AF= 0.00148 (36/24302). AF 95% confidence interval is 0.0011. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf57	NM_001301834.1	c.-16+1G>A		splice_donor_variant, intron_variant	Intron 1 of 3		NP_001288763.1
C12orf57	NM_001301836.2	c.13+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2		NP_001288765.1
RNU7-1	NR_023317.1	n.-153G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf57	ENST00000545581.5	c.-16+1G>A		splice_donor_variant, intron_variant	Intron 1 of 3	3		ENSP00000440602.1
ENSG00000272173	ENST00000607421.2	n.968C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
C12orf57	ENST00000538392.1	n.388+1G>A		splice_donor_variant, intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00113

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000758 AC: 10 AN: 132002 Hom.: 0 AF XY: 0.0000835 AC XY: 6 AN XY: 71898

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.0000844

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 41 AN: 1135690 Hom.: 0 Cov.: 30 AF XY: 0.0000323 AC XY: 18 AN XY: 557070

Gnomad4 AFR exome AF: 0.00148

Gnomad4 AMR exome AF: 0.0000729

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000109

Gnomad4 OTH exome AF: 0.0000482

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74446

Gnomad4 AFR AF: 0.00113

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: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000344 Hom.: 0

Bravo AF: 0.000408

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

C12orf57-related disorder Uncertain:1

Nov 21, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The C12orf57 c.13+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of African descent in gnomAD. In a different transcript in which other splicing variants have been reported with epilepsy and neurodevelopmental disorder phenotypes (NM_138425), this variant is pre-coding (c.-459G>A). Taken together, while this variant could be pathogenic at this time we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.5
DANN	Benign	0.88

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs868972460; hg19: chr12-7052826;