12-50887428-G-T

Position:

• chr12-50887428-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182559.3(TMPRSS12):​c.962G>T​(p.Ser321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPRSS12 NM_182559.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.379

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18286347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS12	NM_182559.3	c.962G>T	p.Ser321Ile	missense_variant	5/5	ENST00000398458.4	NP_872365.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS12	ENST00000398458.4	c.962G>T	p.Ser321Ile	missense_variant	5/5	1	NM_182559.3	ENSP00000381476.3
TMPRSS12	ENST00000551456.5	c.*1872G>T		3_prime_UTR_variant	4/4	2		ENSP00000447259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.962G>T (p.S321I) alteration is located in exon 5 (coding exon 5) of the TMPRSS12 gene. This alteration results from a G to T substitution at nucleotide position 962, causing the serine (S) at amino acid position 321 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	8.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.014	D
Polyphen		0.94	P
Vest4		0.21
MutPred		0.47		Gain of catalytic residue at Q323 (P = 0);
MVP		0.71
MPC		0.21
ClinPred		0.36	T
GERP RS		-0.99
Varity_R		0.079
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-51281211;