NM_001256317.3:c.*287C>T

Variant names:

• chr21-42372475-G-A
• rs757369320
• NM_001256317.3:c.*287C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001256317.3(TMPRSS3):​c.*287C>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 0.000103 in 582,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.202
• Publications: 0 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).

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.*287C>T		3_prime_UTR	Exon 13 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.*287C>T		3_prime_UTR	Exon 13 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032404.3		c.*287C>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.*287C>T		3_prime_UTR	Exon 13 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.*287C>T		3_prime_UTR	Exon 13 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000474596.5	TSL:1	n.1520C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.0000994 AC: 13 AN: 130816 AF XY: 0.0000982

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000123

Gnomad EAS exome AF: 0.0000919

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000103

Gnomad OTH exome AF: 0.000248

GnomAD4 exome AF: 0.000102 AC: 44 AN: 430550 Hom.: 0 Cov.: 0 AF XY: 0.000118 AC XY: 28 AN XY: 236864

African (AFR) AF: 0.00 AC: 0 AN: 12922

American (AMR) AF: 0.00 AC: 0 AN: 31074

Ashkenazi Jewish (ASJ) AF: 0.0000624 AC: 1 AN: 16032

East Asian (EAS) AF: 0.0000508 AC: 1 AN: 19666

South Asian (SAS) AF: 0.000230 AC: 14 AN: 60784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22090

Middle Eastern (MID) AF: 0.00165 AC: 3 AN: 1820

European-Non Finnish (NFE) AF: 0.0000822 AC: 20 AN: 243302

Other (OTH) AF: 0.000219 AC: 5 AN: 22860

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74336

African (AFR) AF: 0.0000965 AC: 4 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68040

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000125

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	-0.93
CADD	Benign	2.3
DANN	Benign	0.62
PhyloP100		0.20

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: rs757369320; hg19: chr21-43792584;