11-118108857-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.544C>G(p.Pro182Ala) variant causes a missense, splice region 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. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPRSS4 NM_019894.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002090
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0240

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=0.17190078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS4	NM_019894.4	c.544C>G	p.Pro182Ala	missense_variant, splice_region_variant	7/13	ENST00000437212.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS4	ENST00000437212.8	c.544C>G	p.Pro182Ala	missense_variant, splice_region_variant	7/13	1	NM_019894.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jun 26, 2023

The c.544C>G (p.P182A) alteration is located in exon 7 (coding exon 7) of the TMPRSS4 gene. This alteration results from a C to G substitution at nucleotide position 544, causing the proline (P) at amino acid position 182 to be replaced by an alanine (A). 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	0.069
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	7.3
Dann	Benign	0.53
DEOGEN2	Benign	0.011	T;T;.;.;.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.58	T;T;T;T;T;.;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T
Polyphen		0.059	B;.;B;B;.;B;.;.
Vest4		0.20
MutPred		0.28		Loss of disorder (P = 0.0813);.;.;.;.;Loss of disorder (P = 0.0813);.;.;
MVP		0.77
MPC		0.13
ClinPred		0.26	T
GERP RS		0.96
Varity_R		0.028
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.040		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: chr11-117979572;