rs139068225

Variant names:

• chr12-6945798-A-G
• rs139068225
• NM_138425.4:c.257A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_138425.4(C12orf57):​c.257A>G​(p.Lys86Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,613,780 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K86Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: C12orf57 NM_138425.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.29
• Publications: 6 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051499456).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00112 (1634/1461550) while in subpopulation NFE AF = 0.00133 (1479/1111896). AF 95% confidence interval is 0.00127. There are 1 homozygotes in GnomAdExome4. There are 806 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	NM_138425.4	MANE Select	c.257A>G	p.Lys86Arg	missense	Exon 3 of 3	NP_612434.1
	C12orf57	NM_001301834.1		c.257A>G	p.Lys86Arg	missense	Exon 4 of 4	NP_001288763.1
	C12orf57	NM_001301836.2		c.218A>G	p.Lys73Arg	missense	Exon 3 of 3	NP_001288765.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C12orf57	ENST00000229281.6	TSL:1 MANE Select	c.257A>G	p.Lys86Arg	missense	Exon 3 of 3	ENSP00000229281.5
	C12orf57	ENST00000545581.5	TSL:3	c.257A>G	p.Lys86Arg	missense	Exon 4 of 4	ENSP00000440602.1
	C12orf57	ENST00000537087.5	TSL:2	c.170A>G	p.Lys57Arg	missense	Exon 3 of 3	ENSP00000440937.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152112 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000596 AC: 149 AN: 250188 AF XY: 0.000665

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.000919

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00112 AC: 1634 AN: 1461550 Hom.: 1 Cov.: 32 AF XY: 0.00111 AC XY: 806 AN XY: 727032

African (AFR) AF: 0.000179 AC: 6 AN: 33476

American (AMR) AF: 0.000358 AC: 16 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86138

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53404

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00133 AC: 1479 AN: 1111896

Other (OTH) AF: 0.00132 AC: 80 AN: 60386

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152230 Hom.: 1 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74444

African (AFR) AF: 0.000193 AC: 8 AN: 41526

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 67998

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00133 Hom.: 5

Bravo AF: 0.000601

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.00104

EpiControl AF: 0.00125

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Temtamy syndrome (2)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.55	N
PhyloP100		7.3
PROVEAN	Benign	0.49	N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T
Sift4G	Benign	0.48	T
Polyphen		0.013	B
Vest4		0.47
MVP		0.82
MPC		0.13
ClinPred		0.040	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.73
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs139068225; hg19: chr12-7054961;