Genetic Variant SCRN3:p.Thr55Ile (chr2-174399926-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_024583.5(SCRN3):c.164C>T(p.Thr55Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000338 in 1,184,176 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T55K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SCRN3
NM_024583.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.85

Publications

2 publications found

Variant links:

Genes affected

SCRN3 (HGNC:30382): (secernin 3) Predicted to enable cysteine-type exopeptidase activity and dipeptidase activity. Predicted to be involved in proteolysis. [provided by Alliance of Genome Resources, Apr 2022]

SCRN3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024583.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCRN3	NM_024583.5	MANE Select	c.164C>T	p.Thr55Ile	missense	Exon 3 of 8	NP_078859.2
SCRN3	NM_001412210.1		c.224C>T	p.Thr75Ile	missense	Exon 3 of 8	NP_001399139.1
SCRN3	NM_001412202.1		c.164C>T	p.Thr55Ile	missense	Exon 3 of 8	NP_001399131.1	Q0VDG4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCRN3	ENST00000272732.11	TSL:1 MANE Select	c.164C>T	p.Thr55Ile	missense	Exon 3 of 8	ENSP00000272732.6	Q0VDG4-1
SCRN3	ENST00000877601.1		c.164C>T	p.Thr55Ile	missense	Exon 3 of 8	ENSP00000547660.1
SCRN3	ENST00000877602.1		c.164C>T	p.Thr55Ile	missense	Exon 3 of 8	ENSP00000547661.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

131140

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

165574

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000338

AC:

AN:

1184176

Hom.:

Cov.:

AF XY:

0.00000507

AC XY:

AN XY:

591396

show subpopulations

African (AFR)

AF:

0.0000437

AC:

AN:

22906

American (AMR)

AF:

0.00

AC:

AN:

21648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20648

East Asian (EAS)

AF:

0.00

AC:

AN:

31058

South Asian (SAS)

AF:

0.00

AC:

AN:

60418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4696

European-Non Finnish (NFE)

AF:

0.00000324

AC:

AN:

925326

Other (OTH)

AF:

0.00

AC:

AN:

49084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

131140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

61794

African (AFR)

AF:

0.00

AC:

AN:

33942

American (AMR)

AF:

0.00

AC:

AN:

12118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3360

East Asian (EAS)

AF:

0.00

AC:

AN:

4706

South Asian (SAS)

AF:

0.00

AC:

AN:

4206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

232

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64002

Other (OTH)

AF:

0.00

AC:

AN:

1726

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.40

MutationAssessor

Pathogenic

3.6

PhyloP100

7.8

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.88

MutPred

0.62

Loss of ubiquitination at K53 (P = 0.0877)

MVP

0.45

MPC

0.23

ClinPred

1.0

GERP RS

5.6

Varity_R

0.84

gMVP

0.87

Mutation Taster

=23/77

disease causing

(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