NM_182559.3:c.384C>A

Variant names:

• chr12-50858785-C-A
• rs373180169
• NM_182559.3:c.384C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_182559.3(TMPRSS12):​c.384C>A​(p.Ser128Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000654 in 1,529,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S128G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: TMPRSS12 NM_182559.3 missense, splice_region
• Scores: Splicing: ADA: 0.00001681
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.621
• Publications: 1 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03840238).
• BP6: Variant 12-50858785-C-A is Benign according to our data. Variant chr12-50858785-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 4187487.Status of the report is criteria_provided_single_submitter, 1 stars.

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.384C>A	p.Ser128Arg	missense splice_region	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.384C>A	p.Ser128Arg	missense splice_region	Exon 3 of 5	ENSP00000381476.3	Q86WS5
	TMPRSS12	ENST00000551456.5	TSL:2	c.384C>A	p.Ser128Arg	missense splice_region	Exon 3 of 4	ENSP00000447259.1	F8WBX2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000526 AC: 1 AN: 190062 AF XY: 0.00000959

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000581 AC: 8 AN: 1377074 Hom.: 0 Cov.: 30 AF XY: 0.00000441 AC XY: 3 AN XY: 680354

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30282

American (AMR) AF: 0.00 AC: 0 AN: 28208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22558

East Asian (EAS) AF: 0.00 AC: 0 AN: 38094

South Asian (SAS) AF: 0.00 AC: 0 AN: 70778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4616

European-Non Finnish (NFE) AF: 0.00000651 AC: 7 AN: 1075924

Other (OTH) AF: 0.0000177 AC: 1 AN: 56484

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00912973), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.092
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.039
DANN	Benign	0.30
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.060	N
PhyloP100		-0.62
PrimateAI	Benign	0.33	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.034
Sift	Benign	0.41	T
Sift4G	Benign	0.70	T
Polyphen		0.0040	B
Vest4		0.17
MutPred		0.46		Gain of catalytic residue at L131 (P = 0)
MVP		0.25
MPC		0.17
ClinPred		0.038	T
GERP RS		-3.4
Varity_R		0.036
gMVP		0.32
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs373180169; hg19: chr12-51252568;