11-130160050-C-T

Variant names:

• chr11-130160050-C-T
• NM_021978.4:c.71C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021978.4(ST14):​c.71C>T​(p.Ser24Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000779 in 1,284,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: ST14 NM_021978.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.743
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2552356).

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.71C>T	p.Ser24Phe	missense	Exon 1 of 19	NP_068813.1	Q9Y5Y6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ST14	ENST00000278742.6	TSL:1 MANE Select	c.71C>T	p.Ser24Phe	missense	Exon 1 of 19	ENSP00000278742.5	Q9Y5Y6
	ST14	ENST00000894129.1		c.71C>T	p.Ser24Phe	missense	Exon 1 of 19	ENSP00000564188.1
	ST14	ENST00000894128.1		c.71C>T	p.Ser24Phe	missense	Exon 1 of 19	ENSP00000564187.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.79e-7 AC: 1 AN: 1284318 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 631780

⚠️ 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: 26008

American (AMR) AF: 0.00 AC: 0 AN: 22884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21812

East Asian (EAS) AF: 0.00 AC: 0 AN: 27498

South Asian (SAS) AF: 0.00 AC: 0 AN: 65436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4246

European-Non Finnish (NFE) AF: 9.81e-7 AC: 1 AN: 1019084

Other (OTH) AF: 0.00 AC: 0 AN: 51934

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.74
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.018	D
Sift4G	Benign	0.28	T
Polyphen		0.74	P
Vest4		0.19
MutPred		0.20		Loss of phosphorylation at S24 (P = 0.0335)
MVP		0.60
MPC		0.67
ClinPred		0.21	T
GERP RS		2.5
PromoterAI		0.39	Neutral
Varity_R		0.12
gMVP		0.25
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

hg19: chr11-130029945;