dbSNP rs137852932: ST14:p.Met1? (chr11-130159982-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_021978.4(ST14):c.3G>A(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ST14
NM_021978.4 start_lost

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.62

Publications

5 publications found

Variant links:

Genes affected

ST14 (HGNC:11344): (ST14 transmembrane serine protease matriptase) The protein encoded by this gene is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine 1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scattering factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors. The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis. [provided by RefSeq, Jul 2008]

ST14 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 11
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet, G2P

ST14 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 94 codons. Genomic position: 130188568. Lost 0.109 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-130159982-G-A is Pathogenic according to our data. Variant chr11-130159982-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4039.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ST14	NM_021978.4 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 19	ENST00000278742.6	NP_068813.1	Q9Y5Y6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ST14	ENST00000278742.6 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 19	1	NM_021978.4	ENSP00000278742.5		Q9Y5Y6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1243402

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

608666

African (AFR)

AF:

0.00

AC:

AN:

25266

American (AMR)

AF:

0.00

AC:

AN:

19708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20252

East Asian (EAS)

AF:

0.00

AC:

AN:

26926

South Asian (SAS)

AF:

0.00

AC:

AN:

58120

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

996020

Other (OTH)

AF:

0.00

AC:

AN:

49708

GnomAD4 genome

Cov.:

Alfa

AF:

0.000580

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Autosomal recessive congenital ichthyosis 11

Pathogenic:1

Jul 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

-0.094

PhyloP100

3.6

PROVEAN

Benign

-0.55

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.38

Vest4

0.71

MutPred

1.0

Gain of catalytic residue at M1 (P = 0.0372);

MVP

0.98

ClinPred

0.82

GERP RS

3.1

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.92

gMVP

0.29

Mutation Taster

=12/188

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over