12-6943656-GACTT-G

Variant names:

• chr12-6943656-GACTT-G
• NM_001301834.1:c.-20_-17delCTTA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001301836.2(C12orf57):​c.9_12delCTTA​(p.Asp3GlufsTer7) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C12orf57 NM_001301836.2 frameshift, splice_region
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.544

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 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.974 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf57	NM_001301834.1	c.-20_-17delCTTA		splice_region_variant	Exon 1 of 4		NP_001288763.1
C12orf57	NM_001301836.2	c.9_12delCTTA	p.Asp3GlufsTer7	frameshift_variant, splice_region_variant	Exon 1 of 3		NP_001288765.1
C12orf57	NM_001301834.1	c.-20_-17delCTTA		5_prime_UTR_variant	Exon 1 of 4		NP_001288763.1
RNU7-1	NR_023317.1	n.-159_-156delACTT		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf57	ENST00000545581.5	c.-20_-17delCTTA		splice_region_variant	Exon 1 of 4	3		ENSP00000440602.1
C12orf57	ENST00000545581	c.-20_-17delCTTA		5_prime_UTR_variant	Exon 1 of 4	3		ENSP00000440602.1
C12orf57	ENST00000538392.1	n.384_387delCTTA		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

C12orf57-related disorder Uncertain:1

Mar 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The C12orf57 c.9_12delCTTA variant is predicted to result in a frameshift and premature protein termination (p.Asp3Glufs*7). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Loss-of-function has not been established as a disease mechanism for this gene, and therefore the clinical significance of this variant is currently uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-7052819;