rs8130564

Variant names:

• chr21-42385547-T-C
• rs8130564
• NM_001256317.3:c.447-13A>G

Your query was ambiguous. Multiple possible variants found:

• chr21-42385547-T-C
• chr21-42385547-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.447-13A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,611,910 control chromosomes in the GnomAD database, including 183,708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (26997 hom., cov: 32)
  • Exomes 𝑓: 0.46 (156711 hom.)
• Consequence: TMPRSS3 NM_001256317.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.76
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 21-42385547-T-C is Benign according to our data. Variant chr21-42385547-T-C is described in ClinVar as Benign. ClinVar VariationId is 46121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.856 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	NM_001256317.3	MANE Select	c.447-13A>G		intron	N/A	NP_001243246.1	P57727-5
	TMPRSS3	NM_024022.4		c.447-13A>G		intron	N/A	NP_076927.1	P57727-1
	TMPRSS3	NM_032405.2		c.447-13A>G		intron	N/A	NP_115781.1	P57727-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.447-13A>G		intron	N/A	ENSP00000494414.1	P57727-5
	TMPRSS3	ENST00000433957.7	TSL:1	c.447-13A>G		intron	N/A	ENSP00000411013.3	P57727-1
	TMPRSS3	ENST00000398397.3	TSL:1	c.447-13A>G		intron	N/A	ENSP00000381434.3	P57727-3

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85622 AN: 151974 Hom.: 26947 Cov.: 32

Gnomad AFR AF: 0.864

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.357

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.477 AC: 119974 AN: 251424 AF XY: 0.474

Gnomad AFR exome AF: 0.876

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.464

Gnomad EAS exome AF: 0.583

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.439

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.457 AC: 666423 AN: 1459818 Hom.: 156711 Cov.: 44 AF XY: 0.457 AC XY: 331939 AN XY: 726302

African (AFR) AF: 0.882 AC: 29499 AN: 33456

American (AMR) AF: 0.419 AC: 18718 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11959 AN: 26122

East Asian (EAS) AF: 0.592 AC: 23476 AN: 39672

South Asian (SAS) AF: 0.514 AC: 44308 AN: 86218

European-Finnish (FIN) AF: 0.366 AC: 19525 AN: 53308

Middle Eastern (MID) AF: 0.514 AC: 2963 AN: 5764

European-Non Finnish (NFE) AF: 0.438 AC: 486494 AN: 1110218

Other (OTH) AF: 0.489 AC: 29481 AN: 60344

GnomAD4 genome AF: 0.564 AC: 85733 AN: 152092 Hom.: 26997 Cov.: 32 AF XY: 0.558 AC XY: 41500 AN XY: 74328

African (AFR) AF: 0.864 AC: 35860 AN: 41518

American (AMR) AF: 0.502 AC: 7679 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1586 AN: 3468

East Asian (EAS) AF: 0.596 AC: 3070 AN: 5152

South Asian (SAS) AF: 0.514 AC: 2472 AN: 4814

European-Finnish (FIN) AF: 0.357 AC: 3778 AN: 10580

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29623 AN: 67954

Other (OTH) AF: 0.563 AC: 1191 AN: 2114

Alfa AF: 0.492 Hom.: 57059

Bravo AF: 0.585

Asia WGS AF: 0.608 AC: 2116 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Autosomal recessive nonsyndromic hearing loss 8 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0010
DANN	Benign	0.25
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8130564; hg19: chr21-43805656; COSMIC: COSV52300140; COSMIC: COSV52300140;