11-118099072-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_019894.4(TMPRSS4):​c.131C>T​(p.Ala44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,613,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/27 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00050 ( 1 hom. )

Consequence

TMPRSS4
NM_019894.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.549
Variant links:
Genes affected
TMPRSS4 (HGNC:11878): (transmembrane serine protease 4) This gene encodes a member of the serine protease family. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified as a gene overexpressed in pancreatic carcinoma. The encoded protein is membrane bound with a N-terminal anchor sequence and a glycosylated extracellular region containing the serine protease domain. The protein has been found to promote SARS-CoV-2 entry into host cells. [provided by RefSeq, Aug 2021]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP6
Variant 11-118099072-C-T is Benign according to our data. Variant chr11-118099072-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1315695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMPRSS4NM_019894.4 linkc.131C>T p.Ala44Val missense_variant Exon 3 of 13 ENST00000437212.8 NP_063947.2 Q9NRS4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMPRSS4ENST00000437212.8 linkc.131C>T p.Ala44Val missense_variant Exon 3 of 13 1 NM_019894.4 ENSP00000416037.3 Q9NRS4-1
TMPRSS4ENST00000522824.5 linkc.131C>T p.Ala44Val missense_variant Exon 3 of 13 1 ENSP00000430547.1 Q9NRS4-2

Frequencies

GnomAD3 genomes
AF:
0.000355
AC:
54
AN:
151980
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000279
AC:
70
AN:
251342
AF XY:
0.000317
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000231
Gnomad NFE exome
AF:
0.000501
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000498
AC:
728
AN:
1461762
Hom.:
1
Cov.:
31
AF XY:
0.000459
AC XY:
334
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
AC:
5
AN:
33478
Gnomad4 AMR exome
AF:
0.000201
AC:
9
AN:
44720
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26132
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.000104
AC:
9
AN:
86250
Gnomad4 FIN exome
AF:
0.000225
AC:
12
AN:
53406
Gnomad4 NFE exome
AF:
0.000567
AC:
630
AN:
1111918
Gnomad4 Remaining exome
AF:
0.000580
AC:
35
AN:
60392
Heterozygous variant carriers
0
35
70
106
141
176
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
26
52
78
104
130
<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:
0.000355
AC:
54
AN:
152098
Hom.:
0
Cov.:
31
AF XY:
0.000350
AC XY:
26
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.000169
AC:
0.000168821
AN:
0.000168821
Gnomad4 AMR
AF:
0.000327
AC:
0.000327268
AN:
0.000327268
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000207
AC:
0.000207297
AN:
0.000207297
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000603
AC:
0.000603172
AN:
0.000603172
Gnomad4 OTH
AF:
0.00
AC:
0
AN:
0
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000387
Hom.:
0
Bravo
AF:
0.000340
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000466
AC:
4
ExAC
AF:
0.000264
AC:
32
EpiCase
AF:
0.000818
EpiControl
AF:
0.000593

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Nov 21, 2019
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Although in silico splice predictors suggest this variant may impact gene splicing, additional in silico analyses, which include protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 30919572) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
21
DANN
Benign
0.36
DEOGEN2
Benign
0.018
T;.;T;.;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.010
N
LIST_S2
Benign
0.64
T;T;.;T;T
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.026
T;T;T;T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.2
L;.;L;L;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.89
.;N;N;N;N
REVEL
Benign
0.24
Sift
Benign
0.49
.;T;T;T;T
Sift4G
Benign
0.87
T;T;T;T;T
Polyphen
0.017
B;B;B;.;.
Vest4
0.18
MVP
0.38
MPC
0.12
ClinPred
0.0026
T
GERP RS
-4.5
Varity_R
0.023
gMVP
0.35
Mutation Taster
=100/0
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.97
Position offset: -2
DS_DL_spliceai
0.98
Position offset: 26

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: rs148550252; hg19: chr11-117969787; COSMIC: COSV99073892; COSMIC: COSV99073892; API