rs1015031347

Variant names:

• chr12-50858800-G-T
• rs1015031347
• NM_182559.3:c.399G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182559.3(TMPRSS12):​c.399G>T​(p.Trp133Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,432,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMPRSS12 NM_182559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

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.399G>T	p.Trp133Cys	missense	Exon 3 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.399G>T	p.Trp133Cys	missense	Exon 3 of 5	ENSP00000381476.3	Q86WS5
	TMPRSS12	ENST00000551456.5	TSL:2	c.399G>T	p.Trp133Cys	missense	Exon 3 of 4	ENSP00000447259.1	F8WBX2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432188 Hom.: 0 Cov.: 30 AF XY: 0.00000281 AC XY: 2 AN XY: 710932

African (AFR) AF: 0.00 AC: 0 AN: 32188

American (AMR) AF: 0.00 AC: 0 AN: 38434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24982

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39264

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5208

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100612

Other (OTH) AF: 0.00 AC: 0 AN: 59096

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-12	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.61		Gain of catalytic residue at A135 (P = 0.0074)
MVP		0.92
MPC		0.82
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.89
gMVP		0.80
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1015031347; hg19: chr12-51252583;