rs397517374

Positions:

• chr21-42388953-C-T
• chr21-42388953-C-G

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.298G>A​(p.Asp100Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D100H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.85

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2525139).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.298G>A	p.Asp100Asn	missense_variant	4/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.298G>A	p.Asp100Asn	missense_variant	4/13
TMPRSS3	NM_032405.2	c.298G>A	p.Asp100Asn	missense_variant	4/9
TMPRSS3	NM_032404.3	c.-84G>A		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.298G>A	p.Asp100Asn	missense_variant	4/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	10
DANN	Benign	0.94
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.69	T;.;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Benign	1.1	L;L;L;.;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.37	T
Polyphen		0.0	B;B;B;.;B
Vest4		0.28, 0.29, 0.28, 0.31
MutPred		0.75		Gain of ubiquitination at K99 (P = 0.0556);Gain of ubiquitination at K99 (P = 0.0556);Gain of ubiquitination at K99 (P = 0.0556);.;Gain of ubiquitination at K99 (P = 0.0556);
MVP		0.82
MPC		0.11
ClinPred		0.16	T
GERP RS		3.4
Varity_R		0.030
gMVP		0.66

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: rs397517374; hg19: chr21-43809062; COSMIC: COSV52306273;