4-68477569-A-G

Position:

• chr4-68477569-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000305363.9(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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin 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 ENST00000305363.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.64

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
TMPRSS11E	NM_014058.4	c.908A>G	p.Tyr303Cys	missense_variant	8/10	ENST00000305363.9	NP_054777.2
TMPRSS11E	XM_011531896.3	c.674A>G	p.Tyr225Cys	missense_variant	7/9		XP_011530198.1
TMPRSS11E	XM_047450139.1	c.674A>G	p.Tyr225Cys	missense_variant	8/10		XP_047306095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS11E	ENST00000305363.9	c.908A>G	p.Tyr303Cys	missense_variant	8/10	1	NM_014058.4	ENSP00000307519	P1
TMPRSS11E	ENST00000510647.1	c.*357A>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	3		ENSP00000424109

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33860 AN: 152040 Hom.: 3879 Cov.: 32

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

GnomAD3 exomes AF: 0.227 AC: 56355 AN: 248700 Hom.: 7139 AF XY: 0.222 AC XY: 29884 AN XY: 134618

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 SAS exome AF: 0.196

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.: 34 AF XY: 0.233 AC XY: 169215 AN XY: 727142

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.0879

Gnomad4 SAS exome AF: 0.200

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.242

Gnomad4 OTH exome AF: 0.211

GnomAD4 genome AF: 0.223 AC: 33882 AN: 152158 Hom.: 3887 Cov.: 32 AF XY: 0.222 AC XY: 16511 AN XY: 74392

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.276

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.0895

Gnomad4 SAS AF: 0.184

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.233

Gnomad4 OTH AF: 0.187

Alfa AF: 0.222 Hom.: 5162

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2019	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	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.050	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.27
Sift	Benign	0.050	D
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.14
MPC		0.45
ClinPred		0.027	T
GERP RS		3.0
Varity_R		0.41
gMVP		0.79

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

Other links and lift over

dbSNP: rs976002; hg19: chr4-69343287; COSMIC: COSV59518900;