Genetic Variant TMPRSS11E:p.Asp277Tyr (chr4-68477490-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_014058.4(TMPRSS11E):c.829G>T(p.Asp277Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TMPRSS11E
NM_014058.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.10

Variant links:

Genes affected

TMPRSS11E (HGNC:24465): (transmembrane serine protease 11E) Predicted to enable serine-type peptidase activity. Involved in cognition. Predicted to be integral component of plasma membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMPRSS11E links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a active_site Charge relay system (size 0) in uniprot entity TM11E_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS11E	NM_014058.4 link	c.829G>T	p.Asp277Tyr	missense_variant	Exon 8 of 10	ENST00000305363.9	NP_054777.2	Q9UL52
TMPRSS11E	XM_011531896.3 link	c.595G>T	p.Asp199Tyr	missense_variant	Exon 7 of 9		XP_011530198.1
TMPRSS11E	XM_047450139.1 link	c.595G>T	p.Asp199Tyr	missense_variant	Exon 8 of 10		XP_047306095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMPRSS11E	ENST00000305363.9 link	c.829G>T	p.Asp277Tyr	missense_variant	Exon 8 of 10	1	NM_014058.4	ENSP00000307519.4	Q9UL52
TMPRSS11E	ENST00000510647.1 link	n.*278G>T		non_coding_transcript_exon_variant	Exon 6 of 6	3		ENSP00000424109.1	H0Y9G7
TMPRSS11E	ENST00000510647.1 link	n.*278G>T		3_prime_UTR_variant	Exon 6 of 6	3		ENSP00000424109.1	H0Y9G7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248656

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134584

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.829G>T (p.D277Y) alteration is located in exon 8 (coding exon 8) of the TMPRSS11E gene. This alteration results from a G to T substitution at nucleotide position 829, causing the aspartic acid (D) at amino acid position 277 to be replaced by a tyrosine (Y). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.86

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-9.0

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.91

Gain of phosphorylation at D277 (P = 0.0078);

MVP

0.98

MPC

0.57

ClinPred

1.0

GERP RS

5.4

Varity_R

0.99

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: 16

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over