Genetic Variant NM_138425.4:c.1A>C (chr12-6944122-A-C) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_138425.4(C12orf57):c.1A>C(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Consequence

C12orf57
NM_138425.4 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.71

Publications

11 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:

ENSG00000272173 (HGNC:):

ENSG00000272173 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 36 codons. Genomic position: 6944529. Lost 0.278 part of the original CDS.

PS1

Another start lost variant in NM_138425.4 (C12orf57) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C12orf57	NM_138425.4	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 3	NP_612434.1	Q99622
C12orf57	NM_001301838.2		c.-201A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001288767.1	U3KQ85
C12orf57	NM_001301834.1		c.1A>C	p.Met1?	initiator_codon	Exon 2 of 4	NP_001288763.1	Q99622

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C12orf57	ENST00000229281.6	TSL:1 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 3	ENSP00000229281.5	Q99622
C12orf57	ENST00000540506.2	TSL:2	c.-201A>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000475635.1	U3KQ85
C12orf57	ENST00000852280.1		c.1A>C	p.Met1?	initiator_codon	Exon 3 of 5	ENSP00000522339.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.030

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.94

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.53

PhyloP100

5.7

PROVEAN

Benign

-0.91

REVEL

Uncertain

0.46

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0070

Vest4

0.94

MutPred

0.57

Gain of catalytic residue at T6 (P = 0.1066)

MVP

0.76

ClinPred

1.0

GERP RS

3.9

PromoterAI

-0.87

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.52

Mutation Taster

=10/190

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over