rs538576531

Variant names:

• chr12-105366661-A-G
• rs538576531
• NM_001145199.2:c.152A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001145199.2(C12orf75):​c.152A>G​(p.Asn51Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000505 in 1,545,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: C12orf75 NM_001145199.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.280
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022331059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C12orf75	NM_001145199.2	c.152A>G	p.Asn51Ser	missense_variant	Exon 4 of 6	ENST00000443585.6	NP_001138671.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C12orf75	ENST00000443585.6	c.152A>G	p.Asn51Ser	missense_variant	Exon 4 of 6	2	NM_001145199.2	ENSP00000448536.2

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000325 AC: 5 AN: 153702 AF XY: 0.0000368

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000655

Gnomad NFE exome AF: 0.0000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 63 AN: 1392682 Hom.: 0 Cov.: 26 AF XY: 0.0000538 AC XY: 37 AN XY: 687422

African (AFR) AF: 0.000127 AC: 4 AN: 31462

American (AMR) AF: 0.0000561 AC: 2 AN: 35620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 35624

South Asian (SAS) AF: 0.0000759 AC: 6 AN: 79012

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000429 AC: 46 AN: 1073192

Other (OTH) AF: 0.0000693 AC: 4 AN: 57730

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74498

African (AFR) AF: 0.000144 AC: 6 AN: 41592

American (AMR) AF: 0.000131 AC: 2 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000775 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000917 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.152A>G (p.N51S) alteration is located in exon 4 (coding exon 4) of the C12orf75 gene. This alteration results from a A to G substitution at nucleotide position 152, causing the asparagine (N) at amino acid position 51 to be replaced by a serine (S). 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	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.29
DANN	Benign	0.67
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.28
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.099
Vest4		0.16
MVP		0.014
ClinPred		0.012	T
GERP RS		-9.5
Mutation Taster		=95/5	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: rs538576531; hg19: chr12-105760439;