Genetic Variant TMPRSS12:p.Arg54Gln (chr12-50843125-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_182559.3(TMPRSS12):c.161G>A(p.Arg54Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000782 in 1,405,850 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. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

TMPRSS12
NM_182559.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0960

Publications

2 publications found

Variant links:

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]

TMPRSS12 links:

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ACMG classification

Classification was made for transcript

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=0.03888905).

BP6

Variant 12-50843125-G-A is Benign according to our data. Variant chr12-50843125-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3808618.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.161G>A	p.Arg54Gln	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.161G>A	p.Arg54Gln	missense	Exon 1 of 5	ENSP00000381476.3	Q86WS5
	TMPRSS12	ENST00000551456.5	TSL:2	c.161G>A	p.Arg54Gln	missense	Exon 1 of 4	ENSP00000447259.1	F8WBX2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000116

AC:

AN:

171992

AF XY:

0.0000109

show subpopulations

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:

0.0000141

Gnomad OTH exome

AF:

0.000217

GnomAD4 exome

AF:

0.00000782

AC:

AN:

1405850

Hom.:

Cov.:

AF XY:

0.00000720

AC XY:

AN XY:

694614

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32368

American (AMR)

AF:

0.00

AC:

AN:

36568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25030

East Asian (EAS)

AF:

0.00

AC:

AN:

37412

South Asian (SAS)

AF:

0.00

AC:

AN:

79094

European-Finnish (FIN)

AF:

0.0000202

AC:

AN:

49504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.00000832

AC:

AN:

1082078

Other (OTH)

AF:

0.0000172

AC:

AN:

58110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000854

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

1.4

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0085

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.39

M_CAP

Benign

0.030

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.58

MutationAssessor

Benign

0.55

PhyloP100

-0.096

PrimateAI

Benign

0.33

PROVEAN

Benign

0.20

REVEL

Benign

0.15

Sift

Benign

0.20

Sift4G

Benign

0.36

Polyphen

0.010

Vest4

0.11

MutPred

0.38

Loss of helix (P = 0.0444)

MVP

0.53

MPC

0.17

ClinPred

0.048

GERP RS

-6.8

PromoterAI

-0.059

Neutral

(source)

Varity_R

0.018

gMVP

0.23

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over