rs35227181

Variant names:

• chr21-42388518-C-T
• rs35227181
• NM_001256317.3:c.331G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-42388518-C-T
• chr21-42388518-C-A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.331G>A​(p.Gly111Ser) variant causes a missense change. The variant allele was found at a frequency of 0.109 in 1,614,026 control chromosomes in the GnomAD database, including 10,204 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G111G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1141 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9063 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.82
• Publications: 22 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 -17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001256317.3
• 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=0.0025500655).
• BP6: Variant 21-42388518-C-T is Benign according to our data. Variant chr21-42388518-C-T is described in ClinVar as Benign. ClinVar VariationId is 46115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 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.331G>A	p.Gly111Ser	missense	Exon 5 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.331G>A	p.Gly111Ser	missense	Exon 5 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032405.2		c.331G>A	p.Gly111Ser	missense	Exon 5 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.331G>A	p.Gly111Ser	missense	Exon 5 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.331G>A	p.Gly111Ser	missense	Exon 5 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000398397.3	TSL:1	c.331G>A	p.Gly111Ser	missense	Exon 5 of 9	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17995 AN: 152054 Hom.: 1138 Cov.: 32

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0823

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.0936 AC: 23532 AN: 251344 AF XY: 0.0925

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0656

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0877

Gnomad NFE exome AF: 0.120

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.108 AC: 157465 AN: 1461854 Hom.: 9063 Cov.: 33 AF XY: 0.107 AC XY: 77635 AN XY: 727228

African (AFR) AF: 0.154 AC: 5166 AN: 33480

American (AMR) AF: 0.0690 AC: 3084 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3210 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39686

South Asian (SAS) AF: 0.0464 AC: 3999 AN: 86258

European-Finnish (FIN) AF: 0.0919 AC: 4908 AN: 53418

Middle Eastern (MID) AF: 0.130 AC: 748 AN: 5768

European-Non Finnish (NFE) AF: 0.117 AC: 129879 AN: 1111994

Other (OTH) AF: 0.107 AC: 6456 AN: 60392

GnomAD4 genome AF: 0.118 AC: 18011 AN: 152172 Hom.: 1141 Cov.: 32 AF XY: 0.115 AC XY: 8533 AN XY: 74394

African (AFR) AF: 0.156 AC: 6463 AN: 41484

American (AMR) AF: 0.103 AC: 1578 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 451 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0367 AC: 177 AN: 4824

European-Finnish (FIN) AF: 0.0823 AC: 871 AN: 10584

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8146 AN: 68016

Other (OTH) AF: 0.127 AC: 268 AN: 2112

Alfa AF: 0.118 Hom.: 2639

Bravo AF: 0.121

TwinsUK AF: 0.114 AC: 422

ALSPAC AF: 0.115 AC: 443

ESP6500AA AF: 0.156 AC: 688

ESP6500EA AF: 0.118 AC: 1011

ExAC AF: 0.0976 AC: 11853

Asia WGS AF: 0.0360 AC: 127 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.123

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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	0.051
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.25
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-2.7	N
PhyloP100		4.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.11
Sift	Benign	0.57	T
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.16
MPC		0.10
ClinPred		0.013	T
GERP RS		4.9
Varity_R		0.071
gMVP		0.47
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs35227181; hg19: chr21-43808627; COSMIC: COSV52301465; COSMIC: COSV52301465;