rs397517372

Positions:

• chr21-42388994-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001256317.3(TMPRSS3):​c.257T>A​(p.Ile86Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I86I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.29

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.257T>A	p.Ile86Asn	missense_variant	4/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.257T>A	p.Ile86Asn	missense_variant	4/13
TMPRSS3	NM_032405.2	c.257T>A	p.Ile86Asn	missense_variant	4/9
TMPRSS3	NM_032404.3	c.-125T>A		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.257T>A	p.Ile86Asn	missense_variant	4/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 17, 2011

The Ile86Asn variant in TMPRSS3 has not been reported in the literature nor previously identified by our laboratory. This residue is conserved across most species, except in rhesus monkey. Computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the Ile86Asn variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. It should be noted that this lab has only sequenced and CDH23 and TMPRSS3 in 24 African American or Black probands and no African American or Black healthy controls. Future analysis could reveal that the Ile86Asn variant is common in this population and therefore unlikely to be pathogenic. In summary, the clinical significance of this variant cannot be determined at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;.;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;.;H
MutationTaster	Benign	0.94	D;D;D;D;D
PrimateAI	Benign	0.46	T
Polyphen		1.0	D;D;D;.;D
Vest4		0.81, 0.80, 0.81, 0.87
MutPred		0.82		Loss of MoRF binding (P = 0.1417);Loss of MoRF binding (P = 0.1417);Loss of MoRF binding (P = 0.1417);.;Loss of MoRF binding (P = 0.1417);
MVP		0.99
MPC		0.71
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517372; hg19: chr21-43809103;