chr21-42376563-G-T

Position:

• chr21-42376563-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001256317.3(TMPRSS3):​c.1169C>A​(p.Thr390Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.937

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity TMPS3_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112853765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.1169C>A	p.Thr390Lys	missense_variant	11/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.1172C>A	p.Thr391Lys	missense_variant	11/13		NP_076927.1
TMPRSS3	NM_032404.3	c.791C>A	p.Thr264Lys	missense_variant	8/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1169C>A	p.Thr390Lys	missense_variant	11/13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461272 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000194 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.6
DANN	Benign	0.50
DEOGEN2	Benign	0.11	.;T;T;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.091	T;.;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.48	.;N;N;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.6	.;.;N;N
REVEL	Benign	0.093
Sift	Benign	1.0	.;.;T;T
Sift4G	Benign	1.0	.;.;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.25, 0.23
MutPred		0.48		.;Gain of ubiquitination at T391 (P = 0.0131);Gain of ubiquitination at T391 (P = 0.0131);.;
MVP		0.54
MPC		0.13
ClinPred		0.024	T
GERP RS		2.6
Varity_R		0.048
gMVP		0.73

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: rs145766262; hg19: chr21-43796672; COSMIC: COSV52308871;