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

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PVS1PM2BS1_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

Scores

2

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.249
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]

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ACMG classification

Classification made for transcript

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
C12orf57NM_001301834.1 linkc.-16+1G>A splice_donor_variant, intron_variant Intron 1 of 3 NP_001288763.1 Q99622
C12orf57NM_001301836.2 linkc.13+1G>A splice_donor_variant, intron_variant Intron 1 of 2 NP_001288765.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
C12orf57ENST00000545581.5 linkc.-16+1G>A splice_donor_variant, intron_variant Intron 1 of 3 3 ENSP00000440602.1 Q99622
ENSG00000272173ENST00000607421.2 linkn.968C>T non_coding_transcript_exon_variant Exon 1 of 1 6
C12orf57ENST00000538392.1 linkn.388+1G>A splice_donor_variant, intron_variant Intron 2 of 2 2
C12orf57ENST00000542222.1 linkn.230+1G>A splice_donor_variant, intron_variant Intron 1 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.000322
AC:
49
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs868972460; hg19: chr12-7052826; API