Genetic Variant C12orf75:p.Ser47Pro (chr12-105366648-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001145199.2(C12orf75):c.139T>C(p.Ser47Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000628 in 1,544,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

C12orf75
NM_001145199.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.07

Publications

1 publications found

Variant links:

Genes affected

C12orf75 (HGNC:35164): (chromosome 12 open reading frame 75)

C12orf75 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015566438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf75	NM_001145199.2 link	c.139T>C	p.Ser47Pro	missense_variant	Exon 4 of 6	ENST00000443585.6	NP_001138671.1	Q8TAD7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf75	ENST00000443585.6 link	c.139T>C	p.Ser47Pro	missense_variant	Exon 4 of 6	2	NM_001145199.2	ENSP00000448536.2		Q8TAD7

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000846

AC:

AN:

153574

AF XY:

0.0000245

show subpopulations

Gnomad AFR exome

AF:

0.00140

Gnomad AMR exome

AF:

0.0000815

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000374

AC:

AN:

1392034

Hom.:

Cov.:

AF XY:

0.0000335

AC XY:

AN XY:

687132

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

31438

American (AMR)

AF:

0.0000562

AC:

AN:

35556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25098

East Asian (EAS)

AF:

0.00

AC:

AN:

35628

South Asian (SAS)

AF:

0.00

AC:

AN:

78976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072730

Other (OTH)

AF:

0.0000866

AC:

AN:

57708

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000295

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000681

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000230

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.139T>C (p.S47P) alteration is located in exon 4 (coding exon 4) of the C12orf75 gene. This alteration results from a T to C substitution at nucleotide position 139, causing the serine (S) at amino acid position 47 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Benign

0.89

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.60

T;T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

1.1

PROVEAN

Uncertain

-4.0

.;D;D

REVEL

Benign

0.25

Sift

Uncertain

0.021

.;D;D

Sift4G

Uncertain

0.058

T;T;D

Vest4

0.57

MVP

0.014

ClinPred

0.038

GERP RS

2.1

gMVP

0.16

Mutation Taster

=90/10

polymorphism

(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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chr12-105366648-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over