chr4-68477569-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014058.4(TMPRSS11E):c.908A>G(p.Tyr303Cys) variant causes a missense change. The variant allele was found at a frequency of 0.233 in 1,613,822 control chromosomes in the GnomAD database, including 45,242 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y303H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 3887 hom., cov: 32)

Exomes 𝑓: 0.23 ( 41355 hom. )

Consequence

TMPRSS11E
NM_014058.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.64

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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005597651).

BP6

Variant 4-68477569-A-G is Benign according to our data. Variant chr4-68477569-A-G is described in ClinVar as [Benign]. Clinvar id is 1249332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS11E	NM_014058.4 link	c.908A>G	p.Tyr303Cys	missense_variant	Exon 8 of 10	ENST00000305363.9	NP_054777.2	Q9UL52
TMPRSS11E	XM_011531896.3 link	c.674A>G	p.Tyr225Cys	missense_variant	Exon 7 of 9		XP_011530198.1
TMPRSS11E	XM_047450139.1 link	c.674A>G	p.Tyr225Cys	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.908A>G	p.Tyr303Cys	missense_variant	Exon 8 of 10	1	NM_014058.4	ENSP00000307519.4	Q9UL52
TMPRSS11E	ENST00000510647.1 link	n.*357A>G		non_coding_transcript_exon_variant	Exon 6 of 6	3		ENSP00000424109.1	H0Y9G7
TMPRSS11E	ENST00000510647.1 link	n.*357A>G		3_prime_UTR_variant	Exon 6 of 6	3		ENSP00000424109.1	H0Y9G7

Frequencies

GnomAD3 genomes

AF:

0.223

AC:

33860

AN:

152040

Hom.:

3879

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.275

Gnomad ASJ

AF:

0.157

Gnomad EAS

AF:

0.0895

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.233

Gnomad OTH

AF:

0.188

GnomAD2 exomes

AF:

0.227

AC:

56355

AN:

248700

AF XY:

0.222

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.348

Gnomad ASJ exome

AF:

0.167

Gnomad EAS exome

AF:

0.0850

Gnomad FIN exome

AF:

0.231

Gnomad NFE exome

AF:

0.228

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.234

AC:

342183

AN:

1461664

Hom.:

41355

Cov.:

AF XY:

0.233

AC XY:

169215

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.202

AC:

6774

AN:

33470

Gnomad4 AMR exome

AF:

0.340

AC:

15225

AN:

44714

Gnomad4 ASJ exome

AF:

0.170

AC:

4433

AN:

26132

Gnomad4 EAS exome

AF:

0.0879

AC:

3490

AN:

39688

Gnomad4 SAS exome

AF:

0.200

AC:

17258

AN:

86246

Gnomad4 FIN exome

AF:

0.236

AC:

12594

AN:

53418

Gnomad4 NFE exome

AF:

0.242

AC:

268972

AN:

1111838

Gnomad4 Remaining exome

AF:

0.211

AC:

12732

AN:

60390

Heterozygous variant carriers

14738

29476

44213

58951

73689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

9208

18416

27624

36832

46040

<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:

0.223

AC:

33882

AN:

152158

Hom.:

3887

Cov.:

AF XY:

0.222

AC XY:

16511

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.213

AC:

0.213046

AN:

0.213046

Gnomad4 AMR

AF:

0.276

AC:

0.275959

AN:

0.275959

Gnomad4 ASJ

AF:

0.157

AC:

0.156846

AN:

0.156846

Gnomad4 EAS

AF:

0.0895

AC:

0.0895264

AN:

0.0895264

Gnomad4 SAS

AF:

0.184

AC:

0.183762

AN:

0.183762

Gnomad4 FIN

AF:

0.231

AC:

0.23074

AN:

0.23074

Gnomad4 NFE

AF:

0.233

AC:

0.233191

AN:

0.233191

Gnomad4 OTH

AF:

0.187

AC:

0.186673

AN:

0.186673

Heterozygous variant carriers

1338

2676

4013

5351

6689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

362

724

1086

1448

1810

<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:

0.225

Hom.:

11863

Bravo

AF:

0.226

TwinsUK

AF:

0.264

AC:

979

ALSPAC

AF:

0.252

AC:

973

ESP6500AA

AF:

0.220

AC:

969

ESP6500EA

AF:

0.231

AC:

1988

ExAC

AF:

0.221

AC:

26864

Asia WGS

AF:

0.128

AC:

445

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 11, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29083408) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.050

MetaRNN

Benign

0.0056

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-4.2

REVEL

Benign

0.27

Sift

Benign

0.050

Sift4G

Benign

0.15

Polyphen

0.99

Vest4

0.14

MPC

0.45

ClinPred

0.027

GERP RS

3.0

Varity_R

0.41

gMVP

0.79

Mutation Taster

=91/9

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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