rs376343239

Variant names:

• chr12-50844019-A-C
• rs376343239
• NM_182559.3:c.365A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-50844019-A-C
• chr12-50844019-A-G
• chr12-50844019-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_182559.3(TMPRSS12):​c.365A>C​(p.His122Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. H122R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPRSS12 NM_182559.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.31

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a active_site Charge relay system (size 0) in uniprot entity TMPSC_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS12	NM_182559.3	c.365A>C	p.His122Pro	missense_variant	Exon 2 of 5	ENST00000398458.4	NP_872365.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS12	ENST00000398458.4	c.365A>C	p.His122Pro	missense_variant	Exon 2 of 5	1	NM_182559.3	ENSP00000381476.3
TMPRSS12	ENST00000551456.5	c.365A>C	p.His122Pro	missense_variant	Exon 2 of 4	2		ENSP00000447259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	.;H
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-9.6	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.80		Gain of catalytic residue at H122 (P = 0);Gain of catalytic residue at H122 (P = 0);
MVP		0.92
MPC		0.82
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs376343239; hg19: chr12-51237802;