rs11203200

Variant names:

• chr21-42394466-G-A
• rs11203200
• NM_001256317.3:c.94+858C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001256317.3(TMPRSS3):​c.94+858C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0938 in 152,172 control chromosomes in the GnomAD database, including 768 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.094 (768 hom., cov: 32)
• Consequence: TMPRSS3 NM_001256317.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.223
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.94+858C>T		intron_variant	Intron 2 of 12	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.94+858C>T		intron_variant	Intron 2 of 12		NP_076927.1
TMPRSS3	NM_032405.2	c.94+858C>T		intron_variant	Intron 2 of 8		NP_115781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.94+858C>T		intron_variant	Intron 2 of 12		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.0938 AC: 14268 AN: 152054 Hom.: 770 Cov.: 32

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0893

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0951

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0938 AC: 14268 AN: 152172 Hom.: 768 Cov.: 32 AF XY: 0.0914 AC XY: 6803 AN XY: 74396

African (AFR) AF: 0.0632 AC: 2621 AN: 41502

American (AMR) AF: 0.0891 AC: 1362 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 387 AN: 3470

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5184

South Asian (SAS) AF: 0.0726 AC: 350 AN: 4824

European-Finnish (FIN) AF: 0.0772 AC: 817 AN: 10578

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8317 AN: 68006

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.115 Hom.: 1868

Bravo AF: 0.0918

Asia WGS AF: 0.0490 AC: 170 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.7
DANN	Benign	0.69
PhyloP100		0.22
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: rs11203200; hg19: chr21-43814575;