11-113690247-C-T

Position:

• chr11-113690247-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_030770.4(TMPRSS5):​c.1190G>A​(p.Arg397Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,552,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: TMPRSS5 NM_030770.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.07

Genes affected

TMPRSS5 (HGNC:14908): (transmembrane serine protease 5) This gene encodes a protein that belongs to the serine protease family. Serine proteases are known to be involved in many physiological and pathological processes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

TMPRSS5 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00740698).
• BP6: Variant 11-113690247-C-T is Benign according to our data. Variant chr11-113690247-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 513900.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS5	NM_030770.4	c.1190G>A	p.Arg397Lys	missense_variant	11/13	ENST00000299882.11	NP_110397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS5	ENST00000299882.11	c.1190G>A	p.Arg397Lys	missense_variant	11/13	1	NM_030770.4	ENSP00000299882.5

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 167 AN: 151620 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.000409 AC: 65 AN: 158806 Hom.: 0 AF XY: 0.000415 AC XY: 35 AN XY: 84256

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.000587

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000478

Gnomad OTH exome AF: 0.000449

GnomAD4 exome AF: 0.000201 AC: 281 AN: 1401104 Hom.: 0 Cov.: 50 AF XY: 0.000214 AC XY: 148 AN XY: 691270

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.00126

Gnomad4 ASJ exome AF: 0.000477

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000777

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00110 AC: 167 AN: 151738 Hom.: 0 Cov.: 28 AF XY: 0.00108 AC XY: 80 AN XY: 74138

Gnomad4 AFR AF: 0.00355

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000737

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000369 Hom.: 1

Bravo AF: 0.00137

ESP6500AA AF: 0.00201 AC: 8

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000232 AC: 25

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 11, 2021	The c.1190G>A (p.R397K) alteration is located in exon 11 (coding exon 11) of the TMPRSS5 gene. This alteration results from a G to A substitution at nucleotide position 1190, causing the arginine (R) at amino acid position 397 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.56
DEOGEN2	Benign	0.11	T;T;T;T;T;.;T;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.71	.;T;T;T;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0074	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.62	N;N;.;.;.;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.33	.;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.69	.;T;T;T;T;T;T;T
Sift4G	Benign	1.0	.;T;T;T;T;T;T;T
Polyphen		0.13	B;B;B;B;.;.;B;.
Vest4		0.085, 0.086, 0.064, 0.065, 0.088, 0.089, 0.080
MVP		0.51
MPC		0.078
ClinPred		0.0022	T
GERP RS		3.5
Varity_R		0.11
gMVP		0.35

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: rs200404888; hg19: chr11-113560969;