11-118111765-C-T

Variant names:

• chr11-118111765-C-T
• rs377614226
• NM_019894.4:c.608C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_019894.4(TMPRSS4):​c.608C>T​(p.Pro203Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P203R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMPRSS4 NM_019894.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.22
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive cerebral atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019894.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS4	NM_019894.4	MANE Select	c.608C>T	p.Pro203Leu	missense	Exon 8 of 13	NP_063947.2	Q9NRS4-1
	TMPRSS4	NM_001173551.2		c.602C>T	p.Pro201Leu	missense	Exon 8 of 13	NP_001167022.2	Q9NRS4-3
	TMPRSS4	NM_001083947.2		c.593C>T	p.Pro198Leu	missense	Exon 8 of 13	NP_001077416.2	Q9NRS4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS4	ENST00000437212.8	TSL:1 MANE Select	c.608C>T	p.Pro203Leu	missense	Exon 8 of 13	ENSP00000416037.3	Q9NRS4-1
	TMPRSS4	ENST00000522824.5	TSL:1	c.593C>T	p.Pro198Leu	missense	Exon 8 of 13	ENSP00000430547.1	Q9NRS4-2
	TMPRSS4	ENST00000714375.1		n.608C>T		non_coding_transcript_exon	Exon 8 of 12	ENSP00000519642.1	A0AAQ5BHV3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.025
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.24
Sift	Uncertain	0.017	D
Sift4G	Benign	0.072	T
Polyphen		0.31	B
Vest4		0.23
MutPred		0.56		Loss of sheet (P = 0.0457)
MVP		0.75
MPC		0.21
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.64
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs377614226; hg19: chr11-117982480;