chr11-118104709-G-T

Variant names:

• chr11-118104709-G-T
• rs772088515
• NM_019894.4:c.329G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019894.4(TMPRSS4):​c.329G>T​(p.Arg110Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R110Q) 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: 4.41
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

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.329G>T	p.Arg110Leu	missense	Exon 5 of 13	NP_063947.2	Q9NRS4-1
	TMPRSS4	NM_001173551.2		c.323G>T	p.Arg108Leu	missense	Exon 5 of 13	NP_001167022.2	Q9NRS4-3
	TMPRSS4	NM_001083947.2		c.329G>T	p.Arg110Leu	missense	Exon 5 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.329G>T	p.Arg110Leu	missense	Exon 5 of 13	ENSP00000416037.3	Q9NRS4-1
	TMPRSS4	ENST00000522824.5	TSL:1	c.329G>T	p.Arg110Leu	missense	Exon 5 of 13	ENSP00000430547.1	Q9NRS4-2
	TMPRSS4	ENST00000714375.1		n.329G>T		non_coding_transcript_exon	Exon 5 of 12	ENSP00000519642.1	A0AAQ5BHV3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.4
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.52		Loss of disorder (P = 0.0676)
MVP		0.76
MPC		0.51
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.46
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 14

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

Other links and lift over

dbSNP: rs772088515; hg19: chr11-117975424;