ENST00000537087:c.-256C>T

Variant names:

• chr12-6943866-C-T
• rs139594532
• ENST00000544681.1:c.-256C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000537087.5(C12orf57):​c.-256C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0038 in 934,242 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (4 hom.)
• Consequence: C12orf57 ENST00000537087.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 0.538
• Publications: 0 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 12-6943866-C-T is Benign according to our data. Variant chr12-6943866-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1202613.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00551 (839/152298) while in subpopulation AFR AF = 0.0128 (532/41570). AF 95% confidence interval is 0.0119. There are 5 homozygotes in GnomAd4. There are 392 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000537087.5. 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+204C>T		intron	N/A	NP_001288763.1	Q99622
	C12orf57	NM_001301836.2		c.13+204C>T		intron	N/A	NP_001288765.1
	RNU7-1	NR_023317.1		n.51C>T		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.-256C>T		5_prime_UTR	Exon 1 of 2	ENSP00000475422.1	U3KQ07
	C12orf57	ENST00000537087.5	TSL:2	c.-256C>T		5_prime_UTR	Exon 1 of 3	ENSP00000440937.1	F5GXW5
	C12orf57	ENST00000921170.1		c.-256C>T		5_prime_UTR	Exon 1 of 2	ENSP00000591229.1

Frequencies

GnomAD3 genomes AF: 0.00545 AC: 830 AN: 152182 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00347 AC: 2711 AN: 781944 Hom.: 4 Cov.: 10 AF XY: 0.00335 AC XY: 1313 AN XY: 391962

African (AFR) AF: 0.0133 AC: 233 AN: 17578

American (AMR) AF: 0.00272 AC: 46 AN: 16904

Ashkenazi Jewish (ASJ) AF: 0.00456 AC: 66 AN: 14458

East Asian (EAS) AF: 0.00253 AC: 70 AN: 27668

South Asian (SAS) AF: 0.000707 AC: 37 AN: 52304

European-Finnish (FIN) AF: 0.000444 AC: 10 AN: 22524

Middle Eastern (MID) AF: 0.00117 AC: 3 AN: 2562

European-Non Finnish (NFE) AF: 0.00355 AC: 2102 AN: 592680

Other (OTH) AF: 0.00408 AC: 144 AN: 35266

GnomAD4 genome AF: 0.00551 AC: 839 AN: 152298 Hom.: 5 Cov.: 33 AF XY: 0.00526 AC XY: 392 AN XY: 74474

African (AFR) AF: 0.0128 AC: 532 AN: 41570

American (AMR) AF: 0.00307 AC: 47 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5178

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00323 AC: 220 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.000160 Hom.: 0

Bravo AF: 0.00641

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
1	-	-	Aicardi-Goutieres syndrome 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.2
DANN	Benign	0.70
PhyloP100		0.54
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.3
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs139594532; hg19: chr12-7053029;