11-118094815-A-G

Variant names:

• chr11-118094815-A-G
• rs2276122
• NM_019894.4:c.4-1A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_019894.4(TMPRSS4):​c.4-1A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,609,458 control chromosomes in the GnomAD database, including 114,738 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.30 (7958 hom., cov: 32)
  • Exomes 𝑓: 0.38 (106780 hom.)
• Consequence: TMPRSS4 NM_019894.4 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0240
• Publications: 24 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 -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0304414 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.6, offset of 0 (no position change), new splice context is: actgactgtttttccttcAGtta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS4	NM_019894.4	c.4-1A>G		splice_acceptor_variant, intron_variant	Intron 1 of 12	ENST00000437212.8	NP_063947.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS4	ENST00000437212.8	c.4-1A>G		splice_acceptor_variant, intron_variant	Intron 1 of 12	1	NM_019894.4	ENSP00000416037.3
TMPRSS4	ENST00000522824.5	c.4-1A>G		splice_acceptor_variant, intron_variant	Intron 1 of 12	1		ENSP00000430547.1
TMPRSS4	ENST00000714375.1	n.4-1A>G		splice_acceptor_variant, intron_variant	Intron 1 of 11			ENSP00000519642.1
TMPRSS4	ENST00000714378.1	n.4-1A>G		splice_acceptor_variant, intron_variant	Intron 1 of 13			ENSP00000519645.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45400 AN: 151896 Hom.: 7953 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.374

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.303

GnomAD2 exomes AF: 0.378 AC: 92629 AN: 245266 AF XY: 0.383

Gnomad AFR exome AF: 0.0903

Gnomad AMR exome AF: 0.480

Gnomad ASJ exome AF: 0.366

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.357

Gnomad NFE exome AF: 0.367

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.377 AC: 549654 AN: 1457444 Hom.: 106780 Cov.: 38 AF XY: 0.380 AC XY: 275530 AN XY: 724652

African (AFR) AF: 0.0895 AC: 2994 AN: 33456

American (AMR) AF: 0.469 AC: 20714 AN: 44136

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9531 AN: 25984

East Asian (EAS) AF: 0.402 AC: 15938 AN: 39620

South Asian (SAS) AF: 0.484 AC: 41285 AN: 85370

European-Finnish (FIN) AF: 0.365 AC: 19423 AN: 53156

Middle Eastern (MID) AF: 0.308 AC: 1776 AN: 5760

European-Non Finnish (NFE) AF: 0.376 AC: 417140 AN: 1109732

Other (OTH) AF: 0.346 AC: 20853 AN: 60230

GnomAD4 genome AF: 0.299 AC: 45409 AN: 152014 Hom.: 7958 Cov.: 32 AF XY: 0.302 AC XY: 22446 AN XY: 74310

African (AFR) AF: 0.102 AC: 4233 AN: 41484

American (AMR) AF: 0.370 AC: 5653 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1291 AN: 3468

East Asian (EAS) AF: 0.373 AC: 1931 AN: 5174

South Asian (SAS) AF: 0.489 AC: 2358 AN: 4822

European-Finnish (FIN) AF: 0.354 AC: 3736 AN: 10544

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25245 AN: 67946

Other (OTH) AF: 0.300 AC: 632 AN: 2104

Alfa AF: 0.348 Hom.: 25301

Bravo AF: 0.290

TwinsUK AF: 0.381 AC: 1411

ALSPAC AF: 0.376 AC: 1451

ESP6500AA AF: 0.110 AC: 485

ESP6500EA AF: 0.367 AC: 3154

ExAC AF: 0.370 AC: 44868

Asia WGS AF: 0.374 AC: 1296 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.0	.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.0	.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		0.024
PROVEAN	Benign	0.0	.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.
Vest4		0.0
GERP RS		0.62
Mutation Taster		=98/2	polymorphism (auto)

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: rs2276122; hg19: chr11-117965530; COSMIC: COSV71108549; COSMIC: COSV71108549;