Genetic Variant TMPRSS4:p.Ala44Gly (chr11-118099072-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019894.4(TMPRSS4):c.131C>G(p.Ala44Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,764 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. A44V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMPRSS4
NM_019894.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.549

Publications

3 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:

LOC105369517 (HGNC:):

LOC105369517 links:

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ACMG classification

Classification was made for transcript

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=0.1320262).

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.131C>G	p.Ala44Gly	missense	Exon 3 of 13	NP_063947.2	Q9NRS4-1
TMPRSS4	NM_001173551.2		c.125C>G	p.Ala42Gly	missense	Exon 3 of 13	NP_001167022.2	Q9NRS4-3
TMPRSS4	NM_001083947.2		c.131C>G	p.Ala44Gly	missense	Exon 3 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.131C>G	p.Ala44Gly	missense	Exon 3 of 13	ENSP00000416037.3	Q9NRS4-1
TMPRSS4	ENST00000522824.5	TSL:1	c.131C>G	p.Ala44Gly	missense	Exon 3 of 13	ENSP00000430547.1	Q9NRS4-2
TMPRSS4	ENST00000714375.1		n.131C>G		non_coding_transcript_exon	Exon 3 of 12	ENSP00000519642.1	A0AAQ5BHV3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251342

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

6.5

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.066

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.69

M_CAP

Benign

0.051

MetaRNN

Benign

0.13

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.2

PhyloP100

-0.55

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.29

Sift

Benign

0.12

Sift4G

Benign

0.13

Polyphen

0.84

Vest4

0.28

MutPred

0.34

Loss of stability (P = 0.0451)

MVP

0.53

MPC

0.14

ClinPred

0.24

GERP RS

-4.5

PromoterAI

-0.040

Neutral

(source)

Varity_R

0.048

gMVP

0.36

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over