Genetic Variant C12orf57:p.Ala43Pro (chr12-6944550-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_138425.4(C12orf57):c.127G>C(p.Ala43Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,782 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A43S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

C12orf57
NM_138425.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.84

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 Gene-Disease associations (from GenCC):

temtamy syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

C12orf57 links:

ENSG00000272173 (HGNC:):

ENSG00000272173 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

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.127G>C	p.Ala43Pro	missense	Exon 2 of 3	NP_612434.1	Q99622
C12orf57	NM_001301834.1		c.127G>C	p.Ala43Pro	missense	Exon 3 of 4	NP_001288763.1	Q99622
C12orf57	NM_001301836.2		c.88G>C	p.Ala30Pro	missense	Exon 2 of 3	NP_001288765.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C12orf57	ENST00000229281.6	TSL:1 MANE Select	c.127G>C	p.Ala43Pro	missense	Exon 2 of 3	ENSP00000229281.5	Q99622
C12orf57	ENST00000852280.1		c.127G>C	p.Ala43Pro	missense	Exon 4 of 5	ENSP00000522339.1
C12orf57	ENST00000545581.5	TSL:3	c.127G>C	p.Ala43Pro	missense	Exon 3 of 4	ENSP00000440602.1	Q99622

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.8

PhyloP100

5.8

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.57

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.020

Polyphen

1.0

Vest4

0.90

MutPred

0.35

Gain of catalytic residue at A43 (P = 3e-04)

MVP

0.97

MPC

0.71

ClinPred

1.0

GERP RS

3.7

PromoterAI

-0.060

Neutral

(source)

Varity_R

0.92

gMVP

0.95

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over