11-118108891-G-C

Position:

• chr11-118108891-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP4_Strong BP6_Moderate BS2

The ENST00000437212.8(TMPRSS4):​c.578G>C​(p.Cys193Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00417 in 1,614,030 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: TMPRSS4 ENST00000437212.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.71

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.030412793).
• BP6: Variant 11-118108891-G-C is Benign according to our data. Variant chr11-118108891-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2642410.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS4	NM_019894.4	c.578G>C	p.Cys193Ser	missense_variant	7/13	ENST00000437212.8	NP_063947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS4	ENST00000437212.8	c.578G>C	p.Cys193Ser	missense_variant	7/13	1	NM_019894.4	ENSP00000416037.3
TMPRSS4	ENST00000522824.5	c.563G>C	p.Cys188Ser	missense_variant	7/13	1		ENSP00000430547.1

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00384 AC: 964 AN: 251000 Hom.: 5 AF XY: 0.00367 AC XY: 498 AN XY: 135644

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000883

Gnomad FIN exome AF: 0.00735

Gnomad NFE exome AF: 0.00526

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00424 AC: 6197 AN: 1461726 Hom.: 18 Cov.: 30 AF XY: 0.00416 AC XY: 3027 AN XY: 727172

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.00210

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.00696

Gnomad4 NFE exome AF: 0.00464

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74478

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00594

Gnomad4 NFE AF: 0.00509

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00443 Hom.: 2

Bravo AF: 0.00351

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00417 AC: 506

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00498

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

TMPRSS4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;.;.;.;T;.;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.58	T;T;T;T;T;.;T;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.030	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-9.6	.;.;D;D;D;D;D;D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	.;.;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;D;.;.
Vest4		0.73
MutPred		0.75		Gain of disorder (P = 0.0089);.;.;.;.;Gain of disorder (P = 0.0089);.;.;
MVP		0.90
MPC		0.63
ClinPred		0.079	T
GERP RS		4.9
Varity_R		0.94
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs45441097; hg19: chr11-117979606;