chr21-42388942-G-T

Position:

• chr21-42388942-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_001256317.3(TMPRSS3):​c.309C>A​(p.Asp103Glu) 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. D103G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.679

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-42388943-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.309C>A	p.Asp103Glu	missense_variant	4/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.309C>A	p.Asp103Glu	missense_variant	4/13		NP_076927.1
TMPRSS3	NM_032405.2	c.309C>A	p.Asp103Glu	missense_variant	4/9		NP_115781.1
TMPRSS3	NM_032404.3	c.-73C>A		5_prime_UTR_variant	1/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.309C>A	p.Asp103Glu	missense_variant	4/13		NM_001256317.3	ENSP00000494414	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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Benign	0.17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	.;D;D;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.83	T;.;T;T;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;H;.;H
MutationTaster	Benign	0.87	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	.;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Uncertain	0.010	.;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.82, 0.83, 0.82, 0.80
MutPred		0.87		Loss of phosphorylation at Y105 (P = 0.1138);Loss of phosphorylation at Y105 (P = 0.1138);Loss of phosphorylation at Y105 (P = 0.1138);.;Loss of phosphorylation at Y105 (P = 0.1138);
MVP		0.88
MPC		0.49
ClinPred		1.0	D
GERP RS		-8.0
Varity_R		0.94
gMVP		0.94

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: rs111033502; hg19: chr21-43809051;