11-118103216-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019894.4(TMPRSS4):c.273C>G(p.His91Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS4 NM_019894.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.355

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
• BP4: Computational evidence support a benign effect (MetaRNN=0.18714026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS4	NM_019894.4	c.273C>G	p.His91Gln	missense_variant	4/13	ENST00000437212.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS4	ENST00000437212.8	c.273C>G	p.His91Gln	missense_variant	4/13	1	NM_019894.4	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2024

The c.273C>G (p.H91Q) alteration is located in exon 4 (coding exon 4) of the TMPRSS4 gene. This alteration results from a C to G substitution at nucleotide position 273, causing the histidine (H) at amino acid position 91 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	7.9
Dann	Benign	0.62
DEOGEN2	Benign	0.022	T;T;.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.35	T;T;T;T;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	N;.;.;.;N;N
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.34	T
Sift4G	Benign	0.31	T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;B;.
Vest4		0.13
MutPred		0.35		Gain of methylation at K94 (P = 0.1346);.;.;.;Gain of methylation at K94 (P = 0.1346);Gain of methylation at K94 (P = 0.1346);
MVP		0.76
MPC		0.12
ClinPred		0.046	T
GERP RS		0.24
Varity_R		0.11
gMVP		0.27

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-117973931;