rs782238229

Variant names:

• chr12-6944532-G-A
• rs782238229
• NM_138425.4:c.109G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138425.4(C12orf57):​c.109G>A​(p.Asp37Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: C12orf57 NM_138425.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.25

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35989472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf57	NM_138425.4	c.109G>A	p.Asp37Asn	missense_variant	Exon 2 of 3	ENST00000229281.6	NP_612434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf57	ENST00000229281.6	c.109G>A	p.Asp37Asn	missense_variant	Exon 2 of 3	1	NM_138425.4	ENSP00000229281.5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152272 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 251018 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135822

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461648 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152390 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74528

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Oct 12, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Temtamy syndrome Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 37 of the C12orf57 protein (p.Asp37Asn). This variant is present in population databases (rs782238229, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with C12orf57-related conditions. ClinVar contains an entry for this variant (Variation ID: 575129). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;T;T;T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.1	L;.;.;L;.
PROVEAN	Benign	-1.4	N;.;N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.16	T;.;D;T;.
Sift4G	Benign	0.072	T;D;T;T;T
Polyphen		0.018	B;.;D;B;.
Vest4		0.29, 0.45, 0.35, 0.34
MutPred		0.23		Loss of disorder (P = 0.2088);Loss of disorder (P = 0.2088);Loss of disorder (P = 0.2088);Loss of disorder (P = 0.2088);.;
MVP		0.87
MPC		0.18
ClinPred		0.71	D
GERP RS		3.7
Varity_R		0.40
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs782238229; hg19: chr12-7053695;