chr12-6944509-C-G

Variant names:

• chr12-6944509-C-G
• rs139938808
• NM_138425.4:c.86C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138425.4(C12orf57):​c.86C>G​(p.Ala29Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign 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. A29V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: C12orf57 NM_138425.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.43
• Publications: 0 publications found

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

ENSG00000272173 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29215264).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	NM_138425.4	MANE Select	c.86C>G	p.Ala29Gly	missense	Exon 2 of 3	NP_612434.1	Q99622
	C12orf57	NM_001301834.1		c.86C>G	p.Ala29Gly	missense	Exon 3 of 4	NP_001288763.1	Q99622
	C12orf57	NM_001301836.2		c.47C>G	p.Ala16Gly	missense	Exon 2 of 3	NP_001288765.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	ENST00000229281.6	TSL:1 MANE Select	c.86C>G	p.Ala29Gly	missense	Exon 2 of 3	ENSP00000229281.5	Q99622
	C12orf57	ENST00000852280.1		c.86C>G	p.Ala29Gly	missense	Exon 4 of 5	ENSP00000522339.1
	C12orf57	ENST00000545581.5	TSL:3	c.86C>G	p.Ala29Gly	missense	Exon 3 of 4	ENSP00000440602.1	Q99622

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461018 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726814

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5246

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.0021
Eigen_PC	Benign	0.072
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.4
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.30
Sift	Benign	0.20	T
Sift4G	Benign	0.42	T
Polyphen		0.10	B
Vest4		0.22
MutPred		0.22		Gain of catalytic residue at A29 (P = 0.0111)
MVP		0.84
MPC		0.23
ClinPred		0.67	D
GERP RS		3.7
PromoterAI		0.0014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.46
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs139938808; hg19: chr12-7053672;