Genetic Variant TMPRSS4:p.Val229Phe (chr11-118111842-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_019894.4(TMPRSS4):c.685G>T(p.Val229Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V229I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TMPRSS4
NM_019894.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.140

Publications

0 publications found

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]

TMPRSS4 Gene-Disease associations (from GenCC):

autosomal recessive cerebral atrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMPRSS4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2719694).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019894.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS4	NM_019894.4	MANE Select	c.685G>T	p.Val229Phe	missense	Exon 8 of 13	NP_063947.2	Q9NRS4-1
TMPRSS4	NM_001173551.2		c.679G>T	p.Val227Phe	missense	Exon 8 of 13	NP_001167022.2	Q9NRS4-3
TMPRSS4	NM_001083947.2		c.670G>T	p.Val224Phe	missense	Exon 8 of 13	NP_001077416.2	Q9NRS4-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS4	ENST00000437212.8	TSL:1 MANE Select	c.685G>T	p.Val229Phe	missense	Exon 8 of 13	ENSP00000416037.3	Q9NRS4-1
TMPRSS4	ENST00000522824.5	TSL:1	c.670G>T	p.Val224Phe	missense	Exon 8 of 13	ENSP00000430547.1	Q9NRS4-2
TMPRSS4	ENST00000714375.1		n.685G>T		non_coding_transcript_exon	Exon 8 of 12	ENSP00000519642.1	A0AAQ5BHV3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1456388

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33158

American (AMR)

AF:

0.00

AC:

AN:

43834

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26004

East Asian (EAS)

AF:

0.00

AC:

AN:

39120

South Asian (SAS)

AF:

0.00

AC:

AN:

85122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109810

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.41

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.31

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.38

M_CAP

Benign

0.035

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.21

PhyloP100

-0.14

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.29

Sift

Uncertain

0.018

Sift4G

Uncertain

0.019

Polyphen

0.0070

Vest4

0.11

MutPred

0.51

Gain of catalytic residue at V229 (P = 0.114)

MVP

0.20

MPC

0.21

ClinPred

0.061

GERP RS

-8.0

Varity_R

0.25

gMVP

0.52

Mutation Taster

=78/22

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over