rs201246220

chr12-6944158-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138425.4(C12orf57):c.37G>A(p.Ala13Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000196 in 1,614,222 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 0.000092 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: C12orf57 NM_138425.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.47

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22601861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C12orf57	NM_138425.4	c.37G>A	p.Ala13Thr	missense_variant	1/3	ENST00000229281.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C12orf57	ENST00000229281.6	c.37G>A	p.Ala13Thr	missense_variant	1/3	1	NM_138425.4	P1
	ENST00000607421.2	n.473C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251446 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.000167

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461862 Hom.: 0 Cov.: 33 AF XY: 0.000191 AC XY: 139 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000267

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152360 Hom.: 0 Cov.: 34 AF XY: 0.0000671 AC XY: 5 AN XY: 74512

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000173 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Temtamy syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 13 of the C12orf57 protein (p.Ala13Thr). This variant is present in population databases (rs201246220, gnomAD 0.02%). 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: 575714). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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	0.10
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.70	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.7	L;.;.;L
MutationTaster	Benign	0.96	D;D
PROVEAN	Benign	-1.3	N;.;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.18	T;.;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.95	P;.;.;P
Vest4		0.54, 0.54, 0.53
MVP		0.89
MPC		0.15
ClinPred		0.34	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201246220; hg19: chr12-7053321;