rs115223836

Variant names:

• chr21-42380208-C-G
• rs115223836
• NM_001256317.3:c.957G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001256317.3(TMPRSS3):​c.957G>C​(p.Met319Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,613,614 control chromosomes in the GnomAD database, including 4 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).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.36
• Publications: 1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• 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 nonsyndromic genetic hearing loss, autosomal recessive nonsyndromic hearing loss 8, hearing loss, autosomal recessive.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008906752).
• BP6: Variant 21-42380208-C-G is Benign according to our data. Variant chr21-42380208-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178548.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00221 (337/152300) while in subpopulation AFR AF = 0.00775 (322/41574). AF 95% confidence interval is 0.00705. There are 3 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.957G>C	p.Met319Ile	missense	Exon 10 of 13	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.957G>C	p.Met319Ile	missense	Exon 10 of 13	NP_076927.1	P57727-1
	TMPRSS3	NM_032404.3		c.576G>C	p.Met192Ile	missense	Exon 7 of 10	NP_115780.1	P57727-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.957G>C	p.Met319Ile	missense	Exon 10 of 13	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.957G>C	p.Met319Ile	missense	Exon 10 of 13	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000474596.5	TSL:1	n.825G>C		non_coding_transcript_exon	Exon 7 of 10

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 331 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00762

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000561 AC: 141 AN: 251136 AF XY: 0.000398

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000216 AC: 315 AN: 1461314 Hom.: 1 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 726988

African (AFR) AF: 0.00768 AC: 257 AN: 33466

American (AMR) AF: 0.000179 AC: 8 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111558

Other (OTH) AF: 0.000646 AC: 39 AN: 60368

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74458

African (AFR) AF: 0.00775 AC: 322 AN: 41574

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000254 Hom.: 0

Bravo AF: 0.00225

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000675 AC: 82

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.18	N
PhyloP100		2.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Benign	0.41	T
Sift4G	Benign	0.46	T
Polyphen		0.011	B
Vest4		0.30
MutPred		0.55		Gain of sheet (P = 0.1945)
MVP		0.60
MPC		0.12
ClinPred		0.0017	T
GERP RS		3.6
Varity_R		0.16
gMVP		0.47
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs115223836; hg19: chr21-43800317;