rs225431

Variant names:

• chr21-42383216-G-A
• rs225431
• NM_001256317.3:c.617-18C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256317.3(TMPRSS3):​c.617-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,834 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (10 hom., cov: 33)
  • Exomes 𝑓: 0.012 (110 hom.)
• Consequence: TMPRSS3 NM_001256317.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.833
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-42383216-G-A is Benign according to our data. Variant chr21-42383216-G-A is described in ClinVar as Benign. ClinVar VariationId is 46125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00899 (1369/152316) while in subpopulation NFE AF = 0.0138 (938/68024). AF 95% confidence interval is 0.0131. There are 10 homozygotes in GnomAd4. There are 629 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.617-18C>T		intron	N/A	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.617-18C>T		intron	N/A	NP_076927.1	P57727-1
	TMPRSS3	NM_032405.2		c.617-18C>T		intron	N/A	NP_115781.1	P57727-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.617-18C>T		intron	N/A	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.617-18C>T		intron	N/A	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000398397.3	TSL:1	c.617-18C>T		intron	N/A	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes AF: 0.00899 AC: 1369 AN: 152198 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00843 AC: 2113 AN: 250742 AF XY: 0.00860

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.0124 AC: 18065 AN: 1461518 Hom.: 110 Cov.: 32 AF XY: 0.0122 AC XY: 8857 AN XY: 727080

African (AFR) AF: 0.00227 AC: 76 AN: 33478

American (AMR) AF: 0.00356 AC: 159 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00358 AC: 309 AN: 86242

European-Finnish (FIN) AF: 0.0136 AC: 726 AN: 53238

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.0144 AC: 16063 AN: 1111872

Other (OTH) AF: 0.0108 AC: 650 AN: 60384

GnomAD4 genome AF: 0.00899 AC: 1369 AN: 152316 Hom.: 10 Cov.: 33 AF XY: 0.00845 AC XY: 629 AN XY: 74464

African (AFR) AF: 0.00241 AC: 100 AN: 41570

American (AMR) AF: 0.00745 AC: 114 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4830

European-Finnish (FIN) AF: 0.0164 AC: 174 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0138 AC: 938 AN: 68024

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0109 Hom.: 3

Bravo AF: 0.00819

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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	7.1
DANN	Benign	0.31
PhyloP100		0.83
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: rs225431; hg19: chr21-43803325;