12-50843118-C-G

Variant names:

• chr12-50843118-C-G
• rs747929698
• NM_182559.3:c.154C>G

Variant summary

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

The NM_182559.3(TMPRSS12):​c.154C>G​(p.Arg52Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,423,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. R52W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TMPRSS12 NM_182559.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.85
• Publications: 0 publications found

Genes affected

TMPRSS12 (HGNC:28779): (transmembrane serine protease 12) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to act upstream of or within binding activity of sperm to zona pellucida and protein processing. Predicted to be located in acrosomal vesicle. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.05260685).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182559.3. 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
	TMPRSS12	NM_182559.3	MANE Select	c.154C>G	p.Arg52Gly	missense	Exon 1 of 5	NP_872365.2	Q86WS5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS12	ENST00000398458.4	TSL:1 MANE Select	c.154C>G	p.Arg52Gly	missense	Exon 1 of 5	ENSP00000381476.3	Q86WS5
	TMPRSS12	ENST00000551456.5	TSL:2	c.154C>G	p.Arg52Gly	missense	Exon 1 of 4	ENSP00000447259.1	F8WBX2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1423444 Hom.: 0 Cov.: 32 AF XY: 0.00000142 AC XY: 1 AN XY: 704404

African (AFR) AF: 0.00 AC: 0 AN: 32874

American (AMR) AF: 0.00 AC: 0 AN: 38054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25428

East Asian (EAS) AF: 0.00 AC: 0 AN: 38100

South Asian (SAS) AF: 0.00 AC: 0 AN: 81276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092540

Other (OTH) AF: 0.0000169 AC: 1 AN: 59000

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.023
DANN	Benign	0.48
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		-4.8
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.26
Sift	Benign	0.18	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.38		Loss of helix (P = 0.0444)
MVP		0.19
MPC		0.19
ClinPred		0.083	T
GERP RS		-5.8
PromoterAI		-0.039	Neutral
Varity_R		0.034
gMVP		0.40
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs747929698; hg19: chr12-51236901; COSMIC: COSV68257008; COSMIC: COSV68257008;