21-42372183-ACC-AC

Variant names:

• chr21-42372183-AC-A
• rs34908991
• NM_001256317.3:c.*578delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001256317.3(TMPRSS3):​c.*578delG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.35 (10727 hom., cov: 0)
  • Exomes 𝑓: 0.40 (25413 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65
• 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 -10 ACMG points.

• BP6: Variant 21-42372183-AC-A is Benign according to our data. Variant chr21-42372183-AC-A is described in ClinVar as Likely_benign. ClinVar VariationId is 340042.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 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.*578delG		3_prime_UTR	Exon 13 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.*578delG		3_prime_UTR	Exon 13 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032404.3		c.*578delG		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.*578delG		3_prime_UTR	Exon 13 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.*578delG		3_prime_UTR	Exon 13 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000474596.5	TSL:1	n.1811delG		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.346 AC: 52532 AN: 151904 Hom.: 10722 Cov.: 0

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.507

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.331

GnomAD2 exomes AF: 0.374 AC: 48875 AN: 130692 AF XY: 0.370

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.442

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.0321

Gnomad FIN exome AF: 0.503

Gnomad NFE exome AF: 0.459

Gnomad OTH exome AF: 0.405

GnomAD4 exome AF: 0.398 AC: 118235 AN: 297062 Hom.: 25413 Cov.: 0 AF XY: 0.386 AC XY: 65165 AN XY: 168628

African (AFR) AF: 0.157 AC: 1310 AN: 8334

American (AMR) AF: 0.441 AC: 11952 AN: 27072

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 4515 AN: 10710

East Asian (EAS) AF: 0.0331 AC: 305 AN: 9206

South Asian (SAS) AF: 0.284 AC: 16857 AN: 59388

European-Finnish (FIN) AF: 0.495 AC: 6093 AN: 12318

Middle Eastern (MID) AF: 0.380 AC: 432 AN: 1138

European-Non Finnish (NFE) AF: 0.459 AC: 71207 AN: 155076

Other (OTH) AF: 0.403 AC: 5564 AN: 13820

GnomAD4 genome AF: 0.346 AC: 52551 AN: 152022 Hom.: 10727 Cov.: 0 AF XY: 0.344 AC XY: 25542 AN XY: 74278

African (AFR) AF: 0.158 AC: 6538 AN: 41472

American (AMR) AF: 0.377 AC: 5755 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1475 AN: 3466

East Asian (EAS) AF: 0.0247 AC: 128 AN: 5182

South Asian (SAS) AF: 0.249 AC: 1200 AN: 4816

European-Finnish (FIN) AF: 0.507 AC: 5347 AN: 10536

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30817 AN: 67954

Other (OTH) AF: 0.327 AC: 691 AN: 2110

Alfa AF: 0.407 Hom.: 2423

Bravo AF: 0.334

Asia WGS AF: 0.145 AC: 507 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hearing loss, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs34908991; hg19: chr21-43792292; COSMIC: COSV52300989;