rs62621285

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021978.4(ST14):c.254G>A(p.Arg85His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0421 in 1,614,070 control chromosomes in the GnomAD database, including 1,982 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.039 ( 227 hom., cov: 33)

Exomes 𝑓: 0.043 ( 1755 hom. )

Consequence

ST14
NM_021978.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.999

Publications

11 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: G2P, Genomics England PanelApp, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ST14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016971529).

BP6

Variant 11-130188542-G-A is Benign according to our data. Variant chr11-130188542-G-A is described in ClinVar as Benign. ClinVar VariationId is 1625929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021978.4. 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
	ST14	NM_021978.4	MANE Select	c.254G>A	p.Arg85His	missense	Exon 3 of 19	NP_068813.1	Q9Y5Y6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ST14	ENST00000278742.6	TSL:1 MANE Select	c.254G>A	p.Arg85His	missense	Exon 3 of 19	ENSP00000278742.5	Q9Y5Y6
ST14	ENST00000894129.1		c.254G>A	p.Arg85His	missense	Exon 3 of 19	ENSP00000564188.1
ST14	ENST00000894128.1		c.254G>A	p.Arg85His	missense	Exon 3 of 19	ENSP00000564187.1

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5876

AN:

152192

Hom.:

228

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00815

Gnomad AMI

AF:

0.0658

Gnomad AMR

AF:

0.114

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0288

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0387

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.0537

AC:

13494

AN:

251338

AF XY:

0.0509

show subpopulations

Gnomad AFR exome

AF:

0.00689

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.0814

Gnomad NFE exome

AF:

0.0416

Gnomad OTH exome

AF:

0.0493

GnomAD4 exome

AF:

0.0425

AC:

62157

AN:

1461760

Hom.:

1755

Cov.:

AF XY:

0.0420

AC XY:

30572

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00559

AC:

187

AN:

33480

American (AMR)

AF:

0.151

AC:

6775

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

513

AN:

26136

East Asian (EAS)

AF:

0.000453

AC:

AN:

39700

South Asian (SAS)

AF:

0.0372

AC:

3205

AN:

86256

European-Finnish (FIN)

AF:

0.0792

AC:

4220

AN:

53298

Middle Eastern (MID)

AF:

0.0160

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0404

AC:

44937

AN:

1112006

Other (OTH)

AF:

0.0366

AC:

2210

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

3906

7811

11717

15622

19528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1736

3472

5208

6944

8680

<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

AF:

0.0386

AC:

5876

AN:

152310

Hom.:

227

Cov.:

AF XY:

0.0412

AC XY:

3071

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00813

AC:

338

AN:

41586

American (AMR)

AF:

0.114

AC:

1748

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0181

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5178

South Asian (SAS)

AF:

0.0280

AC:

135

AN:

4826

European-Finnish (FIN)

AF:

0.0760

AC:

806

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0387

AC:

2634

AN:

68022

Other (OTH)

AF:

0.0393

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

277

554

831

1108

1385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0375

Hom.:

425

Bravo

AF:

0.0408

TwinsUK

AF:

0.0448

AC:

166

ALSPAC

AF:

0.0392

AC:

151

ESP6500AA

AF:

0.00772

AC:

ESP6500EA

AF:

0.0375

AC:

322

ExAC

AF:

0.0493

AC:

5979

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.6

PhyloP100

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.96

REVEL

Uncertain

0.29

Sift

Benign

0.052

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.10

MPC

1.2

ClinPred

0.024

GERP RS

0.52

Varity_R

0.063

gMVP

0.30

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over