NM_001256317.3:c.-51-7G>C

Variant names:

• chr21-42395475-C-G
• rs4920100
• NM_001256317.3:c.-51-7G>C

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.-51-7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0273 in 1,404,954 control chromosomes in the GnomAD database, including 2,054 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (266 hom., cov: 31)
  • Exomes 𝑓: 0.027 (1788 hom.)
• Consequence: TMPRSS3 NM_001256317.3 splice_region, intron
• Scores: Splicing: ADA: 0.00007289
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.147
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-42395475-C-G is Benign according to our data. Variant chr21-42395475-C-G is described in ClinVar as Benign. ClinVar VariationId is 46091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.131 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.-51-7G>C		splice_region intron	N/A	NP_001243246.1
	TMPRSS3	NM_024022.4		c.-51-7G>C		splice_region intron	N/A	NP_076927.1
	TMPRSS3	NM_032405.2		c.-51-7G>C		splice_region intron	N/A	NP_115781.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS3	ENST00000644384.2	MANE Select	c.-51-7G>C		splice_region intron	N/A	ENSP00000494414.1
	TMPRSS3	ENST00000433957.7	TSL:1	c.-51-7G>C		splice_region intron	N/A	ENSP00000411013.3
	TMPRSS3	ENST00000398397.3	TSL:1	c.-51-7G>C		splice_region intron	N/A	ENSP00000381434.3

Frequencies

GnomAD3 genomes AF: 0.0295 AC: 4481 AN: 152092 Hom.: 256 Cov.: 31

Gnomad AFR AF: 0.00908

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0540

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0528 AC: 12554 AN: 237702 AF XY: 0.0437

Gnomad AFR exome AF: 0.00723

Gnomad AMR exome AF: 0.263

Gnomad ASJ exome AF: 0.00154

Gnomad EAS exome AF: 0.000171

Gnomad FIN exome AF: 0.0527

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0364

GnomAD4 exome AF: 0.0271 AC: 33895 AN: 1252746 Hom.: 1788 Cov.: 17 AF XY: 0.0252 AC XY: 15970 AN XY: 633760

African (AFR) AF: 0.00554 AC: 163 AN: 29414

American (AMR) AF: 0.245 AC: 10561 AN: 43110

Ashkenazi Jewish (ASJ) AF: 0.00198 AC: 49 AN: 24710

East Asian (EAS) AF: 0.0000518 AC: 2 AN: 38624

South Asian (SAS) AF: 0.00649 AC: 527 AN: 81208

European-Finnish (FIN) AF: 0.0464 AC: 2455 AN: 52952

Middle Eastern (MID) AF: 0.00242 AC: 13 AN: 5368

European-Non Finnish (NFE) AF: 0.0205 AC: 18941 AN: 923950

Other (OTH) AF: 0.0222 AC: 1184 AN: 53410

GnomAD4 genome AF: 0.0296 AC: 4505 AN: 152208 Hom.: 266 Cov.: 31 AF XY: 0.0323 AC XY: 2407 AN XY: 74414

African (AFR) AF: 0.00905 AC: 376 AN: 41542

American (AMR) AF: 0.136 AC: 2076 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4820

European-Finnish (FIN) AF: 0.0540 AC: 572 AN: 10596

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0204 AC: 1385 AN: 67998

Other (OTH) AF: 0.0237 AC: 50 AN: 2112

Alfa AF: 0.00909 Hom.: 2

Bravo AF: 0.0368

ClinVar

ClinVar submissions as Germline

Significance: 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	-0.82
CADD	Benign	1.4
DANN	Benign	0.38
PhyloP100		0.15
PromoterAI		0.056	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.0
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: rs4920100; hg19: chr21-43815584; COSMIC: COSV52302333;