rs45598239

Variant names:

• chr21-42388983-C-T
• rs45598239
• NM_001256317.3:c.268G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.268G>A​(p.Ala90Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0447 in 1,614,130 control chromosomes in the GnomAD database, including 1,917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (124 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1793 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.28
• Publications: 19 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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=0.0037552118).
• BP6: Variant 21-42388983-C-T is Benign according to our data. Variant chr21-42388983-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0526 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	NM_001256317.3	MANE Select	c.268G>A	p.Ala90Thr	missense	Exon 4 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.268G>A	p.Ala90Thr	missense	Exon 4 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032405.2		c.268G>A	p.Ala90Thr	missense	Exon 4 of 9	NP_115781.1	P57727-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.268G>A	p.Ala90Thr	missense	Exon 4 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.268G>A	p.Ala90Thr	missense	Exon 4 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000398397.3	TSL:1	c.268G>A	p.Ala90Thr	missense	Exon 4 of 9	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4946 AN: 152208 Hom.: 124 Cov.: 33

Gnomad AFR AF: 0.00770

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0331

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0318 AC: 7990 AN: 251426 AF XY: 0.0320

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0520

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0459 AC: 67147 AN: 1461804 Hom.: 1793 Cov.: 33 AF XY: 0.0447 AC XY: 32521 AN XY: 727196

African (AFR) AF: 0.00648 AC: 217 AN: 33480

American (AMR) AF: 0.0154 AC: 690 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 646 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.00610 AC: 526 AN: 86258

European-Finnish (FIN) AF: 0.0408 AC: 2179 AN: 53416

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0545 AC: 60562 AN: 1111932

Other (OTH) AF: 0.0380 AC: 2294 AN: 60396

GnomAD4 genome AF: 0.0325 AC: 4945 AN: 152326 Hom.: 124 Cov.: 33 AF XY: 0.0306 AC XY: 2283 AN XY: 74488

African (AFR) AF: 0.00765 AC: 318 AN: 41576

American (AMR) AF: 0.0185 AC: 283 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4824

European-Finnish (FIN) AF: 0.0331 AC: 351 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0541 AC: 3681 AN: 68036

Other (OTH) AF: 0.0242 AC: 51 AN: 2108

Alfa AF: 0.0467 Hom.: 644

Bravo AF: 0.0310

TwinsUK AF: 0.0518 AC: 192

ALSPAC AF: 0.0516 AC: 199

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.0483 AC: 415

ExAC AF: 0.0330 AC: 4003

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0472

EpiControl AF: 0.0469

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Autosomal recessive nonsyndromic hearing loss 8 (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0038	T
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.47
Sift	Benign	0.60	T
Sift4G	Benign	0.54	T
Polyphen		0.98	D
Vest4		0.24
MPC		0.48
ClinPred		0.038	T
GERP RS		5.2
Varity_R		0.10
gMVP		0.64
Mutation Taster		=96/4	polymorphism (auto)

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: rs45598239; hg19: chr21-43809092;