chr21-42385431-A-C

Variant names:

• chr21-42385431-A-C
• rs876658022
• NM_001256317.3:c.550T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2 PM5 PP2 BP4

The NM_001256317.3(TMPRSS3):​c.550T>G​(p.Leu184Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L184S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.479
• Publications: 0 publications found

Genes affected

TMPRSS3 (HGNC:11877): (transmembrane serine protease 3) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. 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 by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

TMPRSS3 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-42385430-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2907554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 8, nonsyndromic genetic hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2850315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.550T>G	p.Leu184Val	missense_variant	Exon 6 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.550T>G	p.Leu184Val	missense_variant	Exon 6 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.550T>G	p.Leu184Val	missense_variant	Exon 6 of 9		NP_115781.1
TMPRSS3	NM_032404.3	c.169T>G	p.Leu57Val	missense_variant	Exon 3 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.550T>G	p.Leu184Val	missense_variant	Exon 6 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu184Val variant in TMPRSS3 has not been previously reported in individua ls with hearing loss and was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu184Val variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.75
DANN	Benign	0.95
DEOGEN2	Benign	0.081	.;T;T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.79	T;.;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.29	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	2.9	M;M;M;.;M
PhyloP100		-0.48
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.6	.;N;N;N;N
REVEL	Benign	0.22
Sift	Benign	0.055	.;T;T;D;D
Sift4G	Benign	0.081	.;T;T;T;T
Polyphen		0.62	P;P;P;.;P
Vest4		0.46, 0.44, 0.45, 0.49
MutPred		0.51		Loss of stability (P = 0.0904);Loss of stability (P = 0.0904);Loss of stability (P = 0.0904);.;Loss of stability (P = 0.0904);
MVP		0.38
MPC		0.52
ClinPred		0.88	D
GERP RS		-2.5
Varity_R		0.17
gMVP		0.60
Mutation Taster		=92/8	polymorphism

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: rs876658022; hg19: chr21-43805540;