21-42389039-A-G

Position:

• chr21-42389039-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001256317.3(TMPRSS3):​c.212T>C​(p.Phe71Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000253 in 1,614,172 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F71F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (3 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.04

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008987516).
• BP6: Variant 21-42389039-A-G is Benign according to our data. Variant chr21-42389039-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225495.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000335 (51/152360) while in subpopulation EAS AF= 0.00965 (50/5184). AF 95% confidence interval is 0.00752. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.212T>C	p.Phe71Ser	missense_variant	4/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.212T>C	p.Phe71Ser	missense_variant	4/13
TMPRSS3	NM_032405.2	c.212T>C	p.Phe71Ser	missense_variant	4/9
TMPRSS3	NM_032404.3	c.-170T>C		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.212T>C	p.Phe71Ser	missense_variant	4/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152242 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: 0.00962

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000748 AC: 188 AN: 251274 Hom.: 2 AF XY: 0.000721 AC XY: 98 AN XY: 135834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0100

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000244 AC: 357 AN: 1461812 Hom.: 3 Cov.: 32 AF XY: 0.000242 AC XY: 176 AN XY: 727206

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00829

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74518

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00965

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000439 Hom.: 1

Bravo AF: 0.000457

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2021	This variant is associated with the following publications: (PMID: 23958653, 30245029, 25770132, 23967202) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 03, 2016

p.Phe71Ser in exon 4 of TMPRSS3: This variant is not expected to have clinical s ignificance because it has been identified in 1.0% (90/8612) of East Asian chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs185332310). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;T;T;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D;.;D;D;T
MetaRNN	Benign	0.0090	T;T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	0.69	N;N;N;.;N
MutationTaster	Benign	0.90	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.15	.;N;N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.024	.;D;D;D;D
Sift4G	Benign	0.12	.;T;T;T;T
Polyphen		0.99	D;P;P;.;D
Vest4		0.70, 0.70, 0.70, 0.70
MVP		0.95
MPC		0.63
ClinPred		0.076	T
GERP RS		5.1
Varity_R		0.11
gMVP		0.85

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: rs185332310; hg19: chr21-43809148;