11-118098999-C-T

Variant names:

• chr11-118098999-C-T
• rs149423953
• NM_019894.4:c.58C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_019894.4(TMPRSS4):​c.58C>T​(p.Arg20Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: TMPRSS4 NM_019894.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.114
• 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

LOC105369517 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.095389634).

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.58C>T	p.Arg20Cys	missense	Exon 3 of 13	NP_063947.2	Q9NRS4-1
	TMPRSS4	NM_001173551.2		c.52C>T	p.Arg18Cys	missense	Exon 3 of 13	NP_001167022.2	Q9NRS4-3
	TMPRSS4	NM_001083947.2		c.58C>T	p.Arg20Cys	missense	Exon 3 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.58C>T	p.Arg20Cys	missense	Exon 3 of 13	ENSP00000416037.3	Q9NRS4-1
	TMPRSS4	ENST00000522824.5	TSL:1	c.58C>T	p.Arg20Cys	missense	Exon 3 of 13	ENSP00000430547.1	Q9NRS4-2
	TMPRSS4	ENST00000714375.1		n.58C>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000519642.1	A0AAQ5BHV3

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152064 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000877 AC: 22 AN: 250714 AF XY: 0.0000886

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1461238 Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44 AN XY: 726900

African (AFR) AF: 0.00122 AC: 41 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111572

Other (OTH) AF: 0.000133 AC: 8 AN: 60374

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152064 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18 AN XY: 74266

African (AFR) AF: 0.00102 AC: 42 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000326 Hom.: 0

Bravo AF: 0.000389

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.095	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.11
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.022	D
Polyphen		1.0	D
Vest4		0.32
MVP		0.86
MPC		0.17
ClinPred		0.075	T
GERP RS		0.93
PromoterAI		-0.030	Neutral
Varity_R		0.10
gMVP		0.42
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149423953; hg19: chr11-117969714; COSMIC: COSV71110654; COSMIC: COSV71110654;