21-42375754-C-T

Variant names:

• chr21-42375754-C-T
• rs114904237
• NM_001256317.3:c.1306G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_001256317.3(TMPRSS3):​c.1306G>A​(p.Val436Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,613,780 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. V436V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.479
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001256317.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 8, nonsyndromic genetic hearing loss.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008411437).
• BP6: Variant 21-42375754-C-T is Benign according to our data. Variant chr21-42375754-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46103.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00403 (614/152248) while in subpopulation AFR AF = 0.0141 (584/41540). AF 95% confidence interval is 0.0131. There are 6 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	NM_001256317.3	MANE Select	c.1306G>A	p.Val436Ile	missense	Exon 12 of 13	NP_001243246.1
	TMPRSS3	NM_024022.4		c.1309G>A	p.Val437Ile	missense	Exon 12 of 13	NP_076927.1
	TMPRSS3	NM_032404.3		c.928G>A	p.Val310Ile	missense	Exon 9 of 10	NP_115780.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.1306G>A	p.Val436Ile	missense	Exon 12 of 13	ENSP00000494414.1
	TMPRSS3	ENST00000433957.7	TSL:1	c.1309G>A	p.Val437Ile	missense	Exon 12 of 13	ENSP00000411013.3
	TMPRSS3	ENST00000474596.5	TSL:1	n.1177G>A		non_coding_transcript_exon	Exon 9 of 10

Frequencies

GnomAD3 genomes AF: 0.00398 AC: 605 AN: 152130 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000955 AC: 240 AN: 251382 AF XY: 0.000640

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000409 AC: 598 AN: 1461532 Hom.: 6 Cov.: 32 AF XY: 0.000348 AC XY: 253 AN XY: 727078

African (AFR) AF: 0.0148 AC: 494 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53064

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1112010

Other (OTH) AF: 0.00104 AC: 63 AN: 60392

GnomAD4 genome AF: 0.00403 AC: 614 AN: 152248 Hom.: 6 Cov.: 31 AF XY: 0.00395 AC XY: 294 AN XY: 74442

African (AFR) AF: 0.0141 AC: 584 AN: 41540

American (AMR) AF: 0.00124 AC: 19 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00123 Hom.: 3

Bravo AF: 0.00445

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00109 AC: 132

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.5
DANN	Benign	0.95
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.48
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.27
Sift	Benign	0.49	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.36
MPC		0.085
ClinPred		0.0013	T
GERP RS		2.6
Varity_R		0.031
gMVP		0.58
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs114904237; hg19: chr21-43795863;