21-42372007-C-A

Variant names:

• chr21-42372007-C-A
• rs146774207
• NM_001256317.3:c.*755G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001256317.3(TMPRSS3):​c.*755G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 454,574 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (4 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0570
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00385 (586/152362) while in subpopulation NFE AF = 0.00614 (418/68040). AF 95% confidence interval is 0.00566. There are 2 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.*755G>T		3_prime_UTR	Exon 13 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.*755G>T		3_prime_UTR	Exon 13 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032404.3		c.*755G>T		3_prime_UTR	Exon 10 of 10	NP_115780.1	P57727-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.*755G>T		3_prime_UTR	Exon 13 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.*755G>T		3_prime_UTR	Exon 13 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000474596.5	TSL:1	n.1988G>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.00386 AC: 587 AN: 152244 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00309 AC: 422 AN: 136592 AF XY: 0.00302

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00115

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00278

Gnomad NFE exome AF: 0.00644

Gnomad OTH exome AF: 0.00362

GnomAD4 exome AF: 0.00363 AC: 1097 AN: 302212 Hom.: 4 Cov.: 0 AF XY: 0.00336 AC XY: 579 AN XY: 172240

African (AFR) AF: 0.000701 AC: 6 AN: 8554

American (AMR) AF: 0.00114 AC: 31 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10786

East Asian (EAS) AF: 0.00 AC: 0 AN: 9348

South Asian (SAS) AF: 0.000218 AC: 13 AN: 59650

European-Finnish (FIN) AF: 0.00229 AC: 29 AN: 12640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1150

European-Non Finnish (NFE) AF: 0.00598 AC: 950 AN: 158766

Other (OTH) AF: 0.00484 AC: 68 AN: 14044

GnomAD4 genome AF: 0.00385 AC: 586 AN: 152362 Hom.: 2 Cov.: 33 AF XY: 0.00346 AC XY: 258 AN XY: 74496

African (AFR) AF: 0.00123 AC: 51 AN: 41592

American (AMR) AF: 0.00222 AC: 34 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00614 AC: 418 AN: 68040

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00405 Hom.: 0

Bravo AF: 0.00425

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.51
PhyloP100		0.057
Mutation Taster		=100/0	polymorphism

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: rs146774207; hg19: chr21-43792116;