rs201018751

Variant names:

• chr21-42375720-A-C
• NM_001256317.3:c.1340T>G

Your query was ambiguous. Multiple possible variants found:

• chr21-42375720-A-C
• chr21-42375720-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001256317.3(TMPRSS3):​c.1340T>G​(p.Met447Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.54

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 5 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.1340T>G	p.Met447Arg	missense_variant	Exon 12 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.1343T>G	p.Met448Arg	missense_variant	Exon 12 of 13		NP_076927.1
TMPRSS3	NM_032404.3	c.962T>G	p.Met321Arg	missense_variant	Exon 9 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1340T>G	p.Met447Arg	missense_variant	Exon 12 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	.;D;D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.3	.;M;M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.1	.;.;D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0010	.;.;D;D
Polyphen		0.73	P;P;P;P
Vest4		0.75, 0.76
MutPred		0.62		.;Gain of ubiquitination at K453 (P = 0.0499);Gain of ubiquitination at K453 (P = 0.0499);.;
MVP		0.94
MPC		0.17
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-43795829;