chr21-42372353-G-A

Variant names:

• chr21-42372353-G-A
• rs55954914
• NM_001256317.3:c.*409C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.*409C>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 0.0293 in 457,720 control chromosomes in the GnomAD database, including 585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (476 hom., cov: 33)
  • Exomes 𝑓: 0.017 (109 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.01
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-42372353-G-A is Benign according to our data. Variant chr21-42372353-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 340047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 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.*409C>T		3_prime_UTR	Exon 13 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.*409C>T		3_prime_UTR	Exon 13 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032404.3		c.*409C>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.*409C>T		3_prime_UTR	Exon 13 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.*409C>T		3_prime_UTR	Exon 13 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000474596.5	TSL:1	n.1642C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8257 AN: 152078 Hom.: 469 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0427

GnomAD2 exomes AF: 0.0182 AC: 2365 AN: 130124 AF XY: 0.0161

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.000247

Gnomad EAS exome AF: 0.000477

Gnomad FIN exome AF: 0.0430

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0168 AC: 5145 AN: 305524 Hom.: 109 Cov.: 0 AF XY: 0.0147 AC XY: 2549 AN XY: 173848

African (AFR) AF: 0.142 AC: 1233 AN: 8702

American (AMR) AF: 0.0132 AC: 361 AN: 27360

Ashkenazi Jewish (ASJ) AF: 0.000273 AC: 3 AN: 10972

East Asian (EAS) AF: 0.000426 AC: 4 AN: 9400

South Asian (SAS) AF: 0.00791 AC: 472 AN: 59678

European-Finnish (FIN) AF: 0.0381 AC: 476 AN: 12482

Middle Eastern (MID) AF: 0.0137 AC: 16 AN: 1166

European-Non Finnish (NFE) AF: 0.0141 AC: 2280 AN: 161420

Other (OTH) AF: 0.0209 AC: 300 AN: 14344

GnomAD4 genome AF: 0.0544 AC: 8279 AN: 152196 Hom.: 476 Cov.: 33 AF XY: 0.0535 AC XY: 3981 AN XY: 74430

African (AFR) AF: 0.149 AC: 6190 AN: 41510

American (AMR) AF: 0.0243 AC: 371 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00623 AC: 30 AN: 4818

European-Finnish (FIN) AF: 0.0464 AC: 492 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0154 AC: 1044 AN: 68000

Other (OTH) AF: 0.0422 AC: 89 AN: 2108

Alfa AF: 0.0313 Hom.: 43

Bravo AF: 0.0575

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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	-0.91
CADD	Benign	0.87
DANN	Benign	0.44
PhyloP100		-1.0
Mutation Taster		=100/0	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: rs55954914; hg19: chr21-43792462;