chr21-42371985-C-A

Variant names:

• chr21-42371985-C-A
• rs35447393
• NM_001256317.3:c.*777G>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.*777G>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 0.0115 in 454,578 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 33)
  • Exomes 𝑓: 0.012 (42 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00700
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1716/152304) while in subpopulation NFE AF = 0.0198 (1349/68014). AF 95% confidence interval is 0.019. There are 21 homozygotes in GnomAd4. There are 774 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 21 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.*777G>T		3_prime_UTR	Exon 13 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.*777G>T		3_prime_UTR	Exon 13 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032404.3		c.*777G>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.*777G>T		3_prime_UTR	Exon 13 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.*777G>T		3_prime_UTR	Exon 13 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000474596.5	TSL:1	n.2010G>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1716 AN: 152186 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0102 AC: 1390 AN: 136796 AF XY: 0.0102

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.00585

Gnomad ASJ exome AF: 0.000844

Gnomad EAS exome AF: 0.000375

Gnomad FIN exome AF: 0.00464

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0116 AC: 3514 AN: 302274 Hom.: 42 Cov.: 0 AF XY: 0.0111 AC XY: 1916 AN XY: 172276

African (AFR) AF: 0.00444 AC: 38 AN: 8554

American (AMR) AF: 0.00565 AC: 154 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.000927 AC: 10 AN: 10786

East Asian (EAS) AF: 0.000428 AC: 4 AN: 9348

South Asian (SAS) AF: 0.00189 AC: 113 AN: 59648

European-Finnish (FIN) AF: 0.00402 AC: 51 AN: 12698

Middle Eastern (MID) AF: 0.00522 AC: 6 AN: 1150

European-Non Finnish (NFE) AF: 0.0189 AC: 3001 AN: 158770

Other (OTH) AF: 0.00975 AC: 137 AN: 14046

GnomAD4 genome AF: 0.0113 AC: 1716 AN: 152304 Hom.: 21 Cov.: 33 AF XY: 0.0104 AC XY: 774 AN XY: 74478

African (AFR) AF: 0.00370 AC: 154 AN: 41584

American (AMR) AF: 0.00948 AC: 145 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

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

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0198 AC: 1349 AN: 68014

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0179 Hom.: 45

Bravo AF: 0.0111

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.42
PhyloP100		0.0070
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: rs35447393; hg19: chr21-43792094; COSMIC: COSV52306594;