Genetic Variant C12orf57:c.-16+154C>T (chr12-6943816-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001301834.1(C12orf57):c.-16+154C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 833,580 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

C12orf57
NM_001301834.1 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -2.30

Publications

0 publications found

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]

C12orf57 links:

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

RNU7-1 links:

ENSG00000272173 (HGNC:):

ENSG00000272173 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00267 (407/152352) while in subpopulation AFR AF = 0.00712 (296/41588). AF 95% confidence interval is 0.00645. There are 0 homozygotes in GnomAd4. There are 197 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301834.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
C12orf57	NM_001301834.1	c.-16+154C>T	intron	N/A	NP_001288763.1	Q99622
C12orf57	NM_001301836.2	c.13+154C>T	intron	N/A	NP_001288765.1
RNU7-1	NR_023317.1	n.1C>T	non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
C12orf57	ENST00000852280.1		c.-16+154C>T	intron	N/A	ENSP00000522339.1
C12orf57	ENST00000545581.5	TSL:3	c.-16+154C>T	intron	N/A	ENSP00000440602.1	Q99622
RNU7-1	ENST00000458811.1	TSL:6	n.1C>T	non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00265

AC:

404

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000852

Gnomad OTH

AF:

0.00287

GnomAD4 exome

AF:

0.00108

AC:

736

AN:

681228

Hom.:

Cov.:

AF XY:

0.00100

AC XY:

343

AN XY:

342664

show subpopulations

African (AFR)

AF:

0.00796

AC:

123

AN:

15456

American (AMR)

AF:

0.00122

AC:

AN:

14696

Ashkenazi Jewish (ASJ)

AF:

0.00703

AC:

AN:

11672

East Asian (EAS)

AF:

0.000197

AC:

AN:

20282

South Asian (SAS)

AF:

0.000374

AC:

AN:

50824

European-Finnish (FIN)

AF:

0.0000656

AC:

AN:

15234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2192

European-Non Finnish (NFE)

AF:

0.000850

AC:

443

AN:

521280

Other (OTH)

AF:

0.00155

AC:

AN:

29592

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00267

AC:

407

AN:

152352

Hom.:

Cov.:

AF XY:

0.00264

AC XY:

197

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00712

AC:

296

AN:

41588

American (AMR)

AF:

0.00176

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000853

AC:

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00330

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

0.0010

(source)

DANN

Benign

0.65

PhyloP100

-2.3

PromoterAI

0.0063

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over