chr21-42375788-G-C

Position:

• chr21-42375788-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001256317.3(TMPRSS3):​c.1272C>G​(p.Cys424Trp) 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 pathogenic 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. C424R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.210

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 10 ACMG points.

• PM1: In a disulfide_bond (size 28) in uniprot entity TMPS3_HUMAN there are 6 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 chr21-42375790-A-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.1272C>G	p.Cys424Trp	missense_variant	12/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.1275C>G	p.Cys425Trp	missense_variant	12/13		NP_076927.1
TMPRSS3	NM_032404.3	c.894C>G	p.Cys298Trp	missense_variant	9/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1272C>G	p.Cys424Trp	missense_variant	12/13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250956 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135736

Gnomad AFR exome AF: 0.000498

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.000107 AC: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.90	.;D;D;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.82	T;.;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.9	.;H;H;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-10	.;.;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.93, 0.94
MVP		0.78
MPC		0.62
ClinPred		0.98	D
GERP RS		-1.6
Varity_R		0.96
gMVP		0.99

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: rs56178910; hg19: chr21-43795897;