11-118099072-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_019894.4(TMPRSS4):c.131C>T(p.Ala44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,613,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: TMPRSS4 NM_019894.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.549

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 11-118099072-C-T is Benign according to our data. Variant chr11-118099072-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1315695.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS4	NM_019894.4	c.131C>T	p.Ala44Val	missense_variant	3/13	ENST00000437212.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS4	ENST00000437212.8	c.131C>T	p.Ala44Val	missense_variant	3/13	1	NM_019894.4	A1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 151980 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000279 AC: 70 AN: 251342 Hom.: 0 AF XY: 0.000317 AC XY: 43 AN XY: 135840

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000498 AC: 728 AN: 1461762 Hom.: 1 Cov.: 31 AF XY: 0.000459 AC XY: 334 AN XY: 727192

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26 AN XY: 74362

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000818

EpiControl AF: 0.000593

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

GeneDx

Nov 21, 2019

Has not been previously published as pathogenic or benign to our knowledge; Although in silico splice predictors suggest this variant may impact gene splicing, additional in silico analyses, which include protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function; however, in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 30919572) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	21
Dann	Benign	0.36
DEOGEN2	Benign	0.018	T;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.64	T;T;.;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L;.;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.87	T;T;T;T;T
Polyphen		0.017	B;B;B;.;.
Vest4		0.18
MVP		0.38
MPC		0.12
ClinPred		0.0026	T
GERP RS		-4.5
Varity_R		0.023
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -2
DS_DL_spliceai		0.98		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148550252; hg19: chr11-117969787; COSMIC: COSV99073892; COSMIC: COSV99073892;