21-42383168-C-A

Position:

• chr21-42383168-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001256317.3(TMPRSS3):​c.647G>T​(p.Arg216Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R216C) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.14

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a disulfide_bond (size 117) in uniprot entity TMPS3_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-42383169-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 21-42383168-C-A is Pathogenic according to our data. Variant chr21-42383168-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 4946.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr21-42383168-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.647G>T	p.Arg216Leu	missense_variant	8/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.647G>T	p.Arg216Leu	missense_variant	8/13		NP_076927.1
TMPRSS3	NM_032405.2	c.647G>T	p.Arg216Leu	missense_variant	8/9		NP_115781.1
TMPRSS3	NM_032404.3	c.266G>T	p.Arg89Leu	missense_variant	5/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.647G>T	p.Arg216Leu	missense_variant	8/13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;D;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Uncertain	2.4	M;M;M;.;M
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.4	.;D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.98, 0.97, 0.97, 0.94
MutPred		0.95		Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);Loss of disorder (P = 0.0294);.;Loss of disorder (P = 0.0294);
MVP		0.96
MPC		0.59
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs137853000; hg19: chr21-43803277;