21-42395451-C-T

Variant names:

• chr21-42395451-C-T
• rs73372256
• NM_001256317.3:c.-34G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.-34G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 1,565,326 control chromosomes in the GnomAD database, including 1,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (585 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (534 hom.)
• Consequence: TMPRSS3 NM_001256317.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.139
• 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: 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 21-42395451-C-T is Benign according to our data. Variant chr21-42395451-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	NM_001256317.3	MANE Select	c.-34G>A		5_prime_UTR	Exon 2 of 13	NP_001243246.1
	TMPRSS3	NM_024022.4		c.-34G>A		5_prime_UTR	Exon 2 of 13	NP_076927.1
	TMPRSS3	NM_032405.2		c.-34G>A		5_prime_UTR	Exon 2 of 9	NP_115781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.-34G>A		5_prime_UTR	Exon 2 of 13	ENSP00000494414.1
	TMPRSS3	ENST00000433957.7	TSL:1	c.-34G>A		5_prime_UTR	Exon 2 of 13	ENSP00000411013.3
	TMPRSS3	ENST00000398397.3	TSL:1	c.-34G>A		5_prime_UTR	Exon 2 of 9	ENSP00000381434.3

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7284 AN: 152098 Hom.: 585 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0392

GnomAD2 exomes AF: 0.0129 AC: 3216 AN: 249520 AF XY: 0.00943

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000790

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00519 AC: 7328 AN: 1413110 Hom.: 534 Cov.: 24 AF XY: 0.00450 AC XY: 3178 AN XY: 706230

African (AFR) AF: 0.172 AC: 5591 AN: 32550

American (AMR) AF: 0.0110 AC: 488 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.000310 AC: 8 AN: 25826

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39414

South Asian (SAS) AF: 0.000517 AC: 44 AN: 85114

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53334

Middle Eastern (MID) AF: 0.0141 AC: 80 AN: 5668

European-Non Finnish (NFE) AF: 0.000397 AC: 424 AN: 1067932

Other (OTH) AF: 0.0118 AC: 691 AN: 58706

GnomAD4 genome AF: 0.0479 AC: 7287 AN: 152216 Hom.: 585 Cov.: 32 AF XY: 0.0463 AC XY: 3448 AN XY: 74430

African (AFR) AF: 0.164 AC: 6816 AN: 41490

American (AMR) AF: 0.0212 AC: 325 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 68026

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0247 Hom.: 75

Bravo AF: 0.0544

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		-0.14
PromoterAI		-0.10	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs73372256; hg19: chr21-43815560;