rs928302

Variant names:

• chr21-42389975-C-T
• rs928302
• NM_001256317.3:c.157G>A
• TMPRSS3 p.Val53Ile

Your query was ambiguous. Multiple possible variants found:

• chr21-42389975-C-T
• chr21-42389975-C-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.157G>A​(p.Val53Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0762 in 1,613,530 control chromosomes in the GnomAD database, including 5,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (595 hom., cov: 33)
  • Exomes 𝑓: 0.075 (5058 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.02
• Publications: 24 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: 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 nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 8, hearing loss, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0013293326).
• BP6: Variant 21-42389975-C-T is Benign according to our data. Variant chr21-42389975-C-T is described in ClinVar as Benign. ClinVar VariationId is 46105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 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.157G>A	p.Val53Ile	missense	Exon 3 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.157G>A	p.Val53Ile	missense	Exon 3 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032405.2		c.157G>A	p.Val53Ile	missense	Exon 3 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.157G>A	p.Val53Ile	missense	Exon 3 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.157G>A	p.Val53Ile	missense	Exon 3 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000398397.3	TSL:1	c.157G>A	p.Val53Ile	missense	Exon 3 of 9	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12783 AN: 152086 Hom.: 597 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0578

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0766

GnomAD2 exomes AF: 0.0756 AC: 19019 AN: 251458 AF XY: 0.0704

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.192

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0657

Gnomad OTH exome AF: 0.0598

GnomAD4 exome AF: 0.0754 AC: 110158 AN: 1461326 Hom.: 5058 Cov.: 31 AF XY: 0.0730 AC XY: 53084 AN XY: 726984

African (AFR) AF: 0.111 AC: 3699 AN: 33472

American (AMR) AF: 0.101 AC: 4505 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 539 AN: 26136

East Asian (EAS) AF: 0.239 AC: 9487 AN: 39678

South Asian (SAS) AF: 0.0295 AC: 2541 AN: 86250

European-Finnish (FIN) AF: 0.0580 AC: 3095 AN: 53408

Middle Eastern (MID) AF: 0.0340 AC: 196 AN: 5766

European-Non Finnish (NFE) AF: 0.0735 AC: 81714 AN: 1111514

Other (OTH) AF: 0.0726 AC: 4382 AN: 60384

GnomAD4 genome AF: 0.0840 AC: 12781 AN: 152204 Hom.: 595 Cov.: 33 AF XY: 0.0825 AC XY: 6142 AN XY: 74420

African (AFR) AF: 0.109 AC: 4513 AN: 41512

American (AMR) AF: 0.0957 AC: 1464 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.207 AC: 1075 AN: 5184

South Asian (SAS) AF: 0.0344 AC: 166 AN: 4824

European-Finnish (FIN) AF: 0.0578 AC: 612 AN: 10590

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0689 AC: 4687 AN: 68016

Other (OTH) AF: 0.0758 AC: 160 AN: 2110

Alfa AF: 0.0733 Hom.: 2225

Bravo AF: 0.0884

Asia WGS AF: 0.100 AC: 349 AN: 3478

EpiCase AF: 0.0648

EpiControl AF: 0.0642

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.11
Sift	Benign	0.074	T
Sift4G	Benign	0.25	T
Varity_R		0.033
gMVP		0.65
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs928302;

hg19: chr21-43810084;

COSMIC: COSV52301142;

COSMIC: COSV52301142;