rs148550252

Variant names:

• chr11-118099072-C-T
• rs148550252
• NM_019894.4:c.131C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-118099072-C-T
• chr11-118099072-C-A
• chr11-118099072-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BP6_Very_Strong

The NM_019894.4(TMPRSS4):​c.131C>T​(p.Ala44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000485 in 1,613,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/26 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A44T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00050 (1 hom.)
• Consequence: TMPRSS4 NM_019894.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.549
• Publications: 3 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.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 11-118099072-C-T is Benign according to our data. Variant chr11-118099072-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1315695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.131C>T	p.Ala44Val	missense	Exon 3 of 13	NP_063947.2	Q9NRS4-1
	TMPRSS4	NM_001173551.2		c.125C>T	p.Ala42Val	missense	Exon 3 of 13	NP_001167022.2	Q9NRS4-3
	TMPRSS4	NM_001083947.2		c.131C>T	p.Ala44Val	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.131C>T	p.Ala44Val	missense	Exon 3 of 13	ENSP00000416037.3	Q9NRS4-1
	TMPRSS4	ENST00000522824.5	TSL:1	c.131C>T	p.Ala44Val	missense	Exon 3 of 13	ENSP00000430547.1	Q9NRS4-2
	TMPRSS4	ENST00000714375.1		n.131C>T		non_coding_transcript_exon	Exon 3 of 12	ENSP00000519642.1	A0AAQ5BHV3

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 151980 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000279 AC: 70 AN: 251342 AF XY: 0.000317

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000501

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000498 AC: 728 AN: 1461762 Hom.: 1 Cov.: 31 AF XY: 0.000459 AC XY: 334 AN XY: 727192

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.000201 AC: 9 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86250

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53406

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5766

European-Non Finnish (NFE) AF: 0.000567 AC: 630 AN: 1111918

Other (OTH) AF: 0.000580 AC: 35 AN: 60392

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26 AN XY: 74362

African (AFR) AF: 0.000169 AC: 7 AN: 41464

American (AMR) AF: 0.000327 AC: 5 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000264 AC: 32

EpiCase AF: 0.000818

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.36
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.55
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.24
Sift	Benign	0.49	T
Sift4G	Benign	0.87	T
Polyphen		0.017	B
Vest4		0.18
MVP		0.38
MPC		0.12
ClinPred		0.0026	T
GERP RS		-4.5
PromoterAI		0.098	Neutral
Varity_R		0.023
gMVP		0.35
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: -2
DS_DL_spliceai		0.98		Position offset: 26

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

Other links and lift over

dbSNP: rs148550252; hg19: chr11-117969787; COSMIC: COSV99073892; COSMIC: COSV99073892;