Genetic Variant TMPRSS5:p.Leu368Leu (chr11-113690335-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_030770.4(TMPRSS5):c.1102T>C(p.Leu368Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,601,632 control chromosomes in the GnomAD database, including 359,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 42358 hom., cov: 29)

Exomes 𝑓: 0.66 ( 317128 hom. )

Consequence

TMPRSS5
NM_030770.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0150

Variant links:

Genes affected

TMPRSS5 (HGNC:14908): (transmembrane serine protease 5) This gene encodes a protein that belongs to the serine protease family. Serine proteases are known to be involved in many physiological and pathological processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS5 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 11-113690335-A-G is Benign according to our data. Variant chr11-113690335-A-G is described in ClinVar as [Benign]. Clinvar id is 508108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.015 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS5	NM_030770.4 link	c.1102T>C	p.Leu368Leu	synonymous_variant	Exon 11 of 13	ENST00000299882.11	NP_110397.2	Q9H3S3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS5	ENST00000299882.11 link	c.1102T>C	p.Leu368Leu	synonymous_variant	Exon 11 of 13	1	NM_030770.4	ENSP00000299882.5		Q9H3S3

Frequencies

GnomAD3 genomes

AF:

0.738

AC:

111652

AN:

151200

Hom.:

42298

Cov.:

show subpopulations

Gnomad AFR

AF:

0.918

Gnomad AMI

AF:

0.530

Gnomad AMR

AF:

0.756

Gnomad ASJ

AF:

0.708

Gnomad EAS

AF:

0.726

Gnomad SAS

AF:

0.697

Gnomad FIN

AF:

0.632

Gnomad MID

AF:

0.796

Gnomad NFE

AF:

0.649

Gnomad OTH

AF:

0.744

GnomAD3 exomes

AF:

0.688

AC:

159386

AN:

231606

Hom.:

55241

AF XY:

0.680

AC XY:

84907

AN XY:

124954

show subpopulations

Gnomad AFR exome

AF:

0.921

Gnomad AMR exome

AF:

0.770

Gnomad ASJ exome

AF:

0.706

Gnomad EAS exome

AF:

0.717

Gnomad SAS exome

AF:

0.687

Gnomad FIN exome

AF:

0.635

Gnomad NFE exome

AF:

0.638

Gnomad OTH exome

AF:

0.678

GnomAD4 exome

AF:

0.658

AC:

955023

AN:

1450312

Hom.:

317128

Cov.:

AF XY:

0.658

AC XY:

473561

AN XY:

719962

show subpopulations

Gnomad4 AFR exome

AF:

0.930

Gnomad4 AMR exome

AF:

0.765

Gnomad4 ASJ exome

AF:

0.705

Gnomad4 EAS exome

AF:

0.761

Gnomad4 SAS exome

AF:

0.691

Gnomad4 FIN exome

AF:

0.633

Gnomad4 NFE exome

AF:

0.639

Gnomad4 OTH exome

AF:

0.681

GnomAD4 genome

AF:

0.739

AC:

111772

AN:

151320

Hom.:

42358

Cov.:

AF XY:

0.737

AC XY:

54463

AN XY:

73850

show subpopulations

Gnomad4 AFR

AF:

0.918

Gnomad4 AMR

AF:

0.756

Gnomad4 ASJ

AF:

0.708

Gnomad4 EAS

AF:

0.726

Gnomad4 SAS

AF:

0.697

Gnomad4 FIN

AF:

0.632

Gnomad4 NFE

AF:

0.649

Gnomad4 OTH

AF:

0.745

Alfa

AF:

0.685

Hom.:

18450

Bravo

AF:

0.752

Asia WGS

AF:

0.742

AC:

2582

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.68

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

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