rs199711462

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004262.3(TMPRSS11D):​c.268G>A​(p.Glu90Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,606,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E90A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TMPRSS11D
NM_004262.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.502
Variant links:
Genes affected
TMPRSS11D (HGNC:24059): (transmembrane serine protease 11D) This gene encodes a trypsin-like serine protease released from the submucosal serous glands onto mucous membrane. It is a type II integral membrane protein and has 29-38% identity in the sequence of the catalytic region with human hepsin, enteropeptidase, acrosin, and mast cell tryptase. The noncatalytic region has little similarity to other known proteins. This protein may play some biological role in the host defense system on the mucous membrane independently of or in cooperation with other substances in airway mucous or bronchial secretions. This protein facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. [provided by RefSeq, Aug 2021]
UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMPRSS11DNM_004262.3 linkc.268G>A p.Glu90Lys missense_variant Exon 4 of 10 ENST00000283916.11 NP_004253.1 O60235

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMPRSS11DENST00000283916.11 linkc.268G>A p.Glu90Lys missense_variant Exon 4 of 10 1 NM_004262.3 ENSP00000283916.6 O60235

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
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:
0.000479
GnomAD3 exomes
AF:
0.00000823
AC:
2
AN:
243086
Hom.:
0
AF XY:
0.00000763
AC XY:
1
AN XY:
131120
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000308
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000168
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1454070
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
722982
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000234
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152264
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 03, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.268G>A (p.E90K) alteration is located in exon 4 (coding exon 4) of the TMPRSS11D gene. This alteration results from a G to A substitution at nucleotide position 268, causing the glutamic acid (E) at amino acid position 90 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
14
DANN
Benign
0.65
DEOGEN2
Benign
0.19
T
Eigen
Benign
-0.73
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.67
T
M_CAP
Benign
0.0039
T
MetaRNN
Benign
0.036
T
MetaSVM
Benign
-0.95
T
MutationAssessor
Benign
1.5
L
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.73
N
REVEL
Benign
0.084
Sift
Benign
0.88
T
Sift4G
Benign
0.75
T
Polyphen
0.021
B
Vest4
0.20
MutPred
0.32
Gain of MoRF binding (P = 0.0115);
MVP
0.31
MPC
0.10
ClinPred
0.034
T
GERP RS
1.2
Varity_R
0.10
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.46
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.46
Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199711462; hg19: chr4-68708325; API