11-113690332-A-G

Variant names:

• chr11-113690332-A-G
• rs7110736
• NM_030770.4:c.1105T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030770.4(TMPRSS5):​c.1105T>C​(p.Phe369Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 1,600,988 control chromosomes in the GnomAD database, including 359,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.74 (42358 hom., cov: 29)
  • Exomes 𝑓: 0.66 (316934 hom.)
• Consequence: TMPRSS5 NM_030770.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.59

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9205406E-6).
• BP6: Variant 11-113690332-A-G is Benign according to our data. Variant chr11-113690332-A-G is described in ClinVar as [Benign]. Clinvar id is 508109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS5	NM_030770.4	c.1105T>C	p.Phe369Leu	missense_variant	Exon 11 of 13	ENST00000299882.11	NP_110397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS5	ENST00000299882.11	c.1105T>C	p.Phe369Leu	missense_variant	Exon 11 of 13	1	NM_030770.4	ENSP00000299882.5

Frequencies

GnomAD3 genomes AF: 0.738 AC: 111659 AN: 151238 Hom.: 42298 Cov.: 29

Gnomad AFR AF: 0.918

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.708

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.796

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.688 AC: 158564 AN: 230546 Hom.: 54908 AF XY: 0.679 AC XY: 84420 AN XY: 124288

Gnomad AFR exome AF: 0.921

Gnomad AMR exome AF: 0.769

Gnomad ASJ exome AF: 0.705

Gnomad EAS exome AF: 0.716

Gnomad SAS exome AF: 0.686

Gnomad FIN exome AF: 0.635

Gnomad NFE exome AF: 0.638

Gnomad OTH exome AF: 0.678

GnomAD4 exome AF: 0.658 AC: 954522 AN: 1449630 Hom.: 316934 Cov.: 61 AF XY: 0.658 AC XY: 473230 AN XY: 719484

Gnomad4 AFR exome AF: 0.930

Gnomad4 AMR exome AF: 0.765

Gnomad4 ASJ exome AF: 0.704

Gnomad4 EAS exome AF: 0.761

Gnomad4 SAS exome AF: 0.690

Gnomad4 FIN exome AF: 0.633

Gnomad4 NFE exome AF: 0.639

Gnomad4 OTH exome AF: 0.681

GnomAD4 genome AF: 0.739 AC: 111779 AN: 151358 Hom.: 42358 Cov.: 29 AF XY: 0.737 AC XY: 54476 AN XY: 73880

Gnomad4 AFR AF: 0.918

Gnomad4 AMR AF: 0.756

Gnomad4 ASJ AF: 0.708

Gnomad4 EAS AF: 0.726

Gnomad4 SAS AF: 0.696

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.649

Gnomad4 OTH AF: 0.745

Alfa AF: 0.668 Hom.: 53565

Bravo AF: 0.752

TwinsUK AF: 0.636 AC: 2357

ALSPAC AF: 0.658 AC: 2535

ESP6500AA AF: 0.914 AC: 3868

ESP6500EA AF: 0.648 AC: 5487

ExAC AF: 0.673 AC: 81025

Asia WGS AF: 0.743 AC: 2583 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.10	T;T;T;T;T;.;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.032	.;T;T;T;T;T;T;T
MetaRNN	Benign	0.0000019	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.53	N;N;.;.;.;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	2.3	.;N;N;N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.52	.;T;T;T;T;T;T;T
Sift4G	Benign	0.53	.;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;.;B;.
Vest4		0.053, 0.049, 0.013, 0.0070, 0.047, 0.046, 0.034
MutPred		0.21		Loss of catalytic residue at F369 (P = 0.027);Loss of catalytic residue at F369 (P = 0.027);.;.;.;.;.;.;
MPC		0.081
ClinPred		0.0027	T
GERP RS		3.2
Varity_R		0.060
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs7110736; hg19: chr11-113561054; COSMIC: COSV55423815; COSMIC: COSV55423815;