chr11-113690357-C-T

Position:

• chr11-113690357-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030770.4(TMPRSS5):​c.1080G>A​(p.Met360Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,453,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: TMPRSS5 NM_030770.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.97

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06496179).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS5	NM_030770.4	c.1080G>A	p.Met360Ile	missense_variant	11/13	ENST00000299882.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS5	ENST00000299882.11	c.1080G>A	p.Met360Ile	missense_variant	11/13	1	NM_030770.4	P2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453738 Hom.: 0 Cov.: 34 AF XY: 0.00000415 AC XY: 3 AN XY: 722038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000461

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.1080G>A (p.M360I) 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 1080, causing the methionine (M) at amino acid position 360 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	3.6
DANN	Benign	0.78
DEOGEN2	Benign	0.073	T;T;T;T;T;.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.061	N
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-1.5	N;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
Polyphen		0.0010	B;B;B;B;.;.;B;.
Vest4		0.097, 0.10, 0.11, 0.10, 0.16, 0.17
MutPred		0.40		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;.;.;.;
MVP		0.55
MPC		0.079
ClinPred		0.038	T
GERP RS		-3.7
Varity_R		0.092
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1310779570; hg19: chr11-113561079;