rs111033261

Positions:

• chr21-42380123-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4_Strong BP6 BS2_Supporting

The NM_001256317.3(TMPRSS3):​c.1042G>A​(p.Asp348Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,613,926 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 4.29

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity TMPS3_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_001256317.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.018525064).
• BP6: Variant 21-42380123-C-T is Benign according to our data. Variant chr21-42380123-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 46094.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr21-42380123-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.1042G>A	p.Asp348Asn	missense_variant	10/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.1042G>A	p.Asp348Asn	missense_variant	10/13		NP_076927.1
TMPRSS3	NM_032404.3	c.661G>A	p.Asp221Asn	missense_variant	7/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1042G>A	p.Asp348Asn	missense_variant	10/13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000713 AC: 179 AN: 251076 Hom.: 0 AF XY: 0.000663 AC XY: 90 AN XY: 135698

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.00121 AC: 1764 AN: 1461560 Hom.: 3 Cov.: 31 AF XY: 0.00114 AC XY: 832 AN XY: 727066

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00147

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 39 AN XY: 74518

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000850

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.00120

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 02, 2022	BS1_supporting -

Autosomal recessive nonsyndromic hearing loss 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2019

The p.Asp348Asn variant in TMPRSS3 is classified as likely benign because it has been identified in 0.1% (145/128962) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), and computational prediction tools predict that this variant does not impact the protein. Although it has been identified by our laboratory in 8 individuals with hearing loss, none of these individuals carried a second TMPRSS3 variant, and 1 individual had an alternate genetic etiology. ACMG/AMP Criteria applied: BS1_Supporting, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	.;T;T;.
Eigen	Benign	-0.028
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;.;T;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	-0.45	N;N;N;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	.;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0080	.;D;D;D
Sift4G	Benign	0.062	.;T;T;T
Polyphen		0.33	B;B;B;P
Vest4		0.29, 0.30
MVP		0.79
MPC		0.36
ClinPred		0.037	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.43
gMVP		0.62

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: rs111033261; hg19: chr21-43800232;