11-118113273-C-T

Variant names:

• chr11-118113273-C-T
• rs1947368020
• NM_019894.4:c.748C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019894.4(TMPRSS4):​c.748C>T​(p.His250Tyr) 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: 31)
• Consequence: TMPRSS4 NM_019894.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0770

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060915083).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS4	NM_019894.4	c.748C>T	p.His250Tyr	missense_variant	Exon 9 of 13	ENST00000437212.8	NP_063947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS4	ENST00000437212.8	c.748C>T	p.His250Tyr	missense_variant	Exon 9 of 13	1	NM_019894.4	ENSP00000416037.3
TMPRSS4	ENST00000522824.5	c.733C>T	p.His245Tyr	missense_variant	Exon 9 of 13	1		ENSP00000430547.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.748C>T (p.H250Y) alteration is located in exon 9 (coding exon 9) of the TMPRSS4 gene. This alteration results from a C to T substitution at nucleotide position 748, causing the histidine (H) at amino acid position 250 to be replaced by a tyrosine (Y). 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	0.066
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.18
DANN	Benign	0.21
DEOGEN2	Benign	0.077	T;T;.;.;.;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.56	T;T;T;T;T;.;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.061	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.48	N;.;.;.;.;N;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.83	.;.;N;N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.34	.;.;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0020	B;.;B;B;.;B;.
Vest4		0.21
MutPred		0.49		Loss of methylation at R248 (P = 0.0668);.;.;.;.;Loss of methylation at R248 (P = 0.0668);.;
MVP		0.23
MPC		0.14
ClinPred		0.24	T
GERP RS		-3.6
Varity_R		0.050
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs1947368020; hg19: chr11-117983988;