rs147231991

Variant names:

• chr21-42388436-G-T
• rs147231991
• NM_001256317.3:c.413C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-42388436-G-T
• chr21-42388436-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 11P and 2B. PM1 PP2 PP5_Very_Strong BP4 BS1_Supporting

The NM_001256317.3(TMPRSS3):​c.413C>A​(p.Ala138Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00195 in 1,614,240 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A138T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (1 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28
• Conservation: PhyloP100: 5.34
• Publications: 32 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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.
• PP5: Variant 21-42388436-G-T is Pathogenic according to our data. Variant chr21-42388436-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 46119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09016231). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00203 (2964/1461892) while in subpopulation NFE AF = 0.00252 (2799/1112012). AF 95% confidence interval is 0.00244. There are 1 homozygotes in GnomAdExome4. There are 1397 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.413C>A	p.Ala138Glu	missense	Exon 5 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.413C>A	p.Ala138Glu	missense	Exon 5 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032405.2		c.413C>A	p.Ala138Glu	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.413C>A	p.Ala138Glu	missense	Exon 5 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.413C>A	p.Ala138Glu	missense	Exon 5 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000398397.3	TSL:1	c.413C>A	p.Ala138Glu	missense	Exon 5 of 9	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000919 AC: 231 AN: 251450 AF XY: 0.000912

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00203 AC: 2964 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.00192 AC XY: 1397 AN XY: 727246

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000648 AC: 29 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00252 AC: 2799 AN: 1112012

Other (OTH) AF: 0.00137 AC: 83 AN: 60396

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74500

African (AFR) AF: 0.000337 AC: 14 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00153 Hom.: 2

Bravo AF: 0.00100

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000799 AC: 97

EpiCase AF: 0.00240

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
14	-	-	Autosomal recessive nonsyndromic hearing loss 8 (14)
10	-	-	not provided (10)
1	-	-	Hearing impairment (1)
1	-	-	Nonsyndromic genetic hearing loss (1)
1	-	-	Rare genetic deafness (1)
1	-	-	TMPRSS3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.090	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.89	P
Vest4		0.62
MVP		0.91
MPC		0.49
ClinPred		0.65	D
GERP RS		4.0
Varity_R		0.77
gMVP		0.89
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs147231991; hg19: chr21-43808545;