22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 4P and 10B. PVS1_StrongBP6_ModerateBS1BS2
The NM_001374504.1(TMPRSS6):c.1842-11_1842-2dupCCCCACCCCA variant causes a splice acceptor, intron change. Variant has been reported in ClinVar as Likely benign (★).
Frequency
Genomes: 𝑓 0.024 ( 92 hom., cov: 0)
Exomes 𝑓: 0.0014 ( 11 hom. )
Failed GnomAD Quality Control
Consequence
TMPRSS6
NM_001374504.1 splice_acceptor, intron
NM_001374504.1 splice_acceptor, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.94
Publications
2 publications found
Genes affected
TMPRSS6 (HGNC:16517): (transmembrane serine protease 6) The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
TMPRSS6 Gene-Disease associations (from GenCC):
- IRIDA syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Likely_benign. The variant received -6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11290992 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 0 (no position change), new splice context is: cccaccccaccccaccccAGcat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
BP6
Variant 22-37069345-C-CTGGGGTGGGG is Benign according to our data. Variant chr22-37069345-C-CTGGGGTGGGG is described in ClinVar as [Likely_benign]. Clinvar id is 786381.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00144 (471/327516) while in subpopulation AFR AF = 0.033 (323/9802). AF 95% confidence interval is 0.03. There are 11 homozygotes in GnomAdExome4. There are 204 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 11 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMPRSS6 | NM_001374504.1 | c.1842-11_1842-2dupCCCCACCCCA | splice_acceptor_variant, intron_variant | Intron 15 of 17 | ENST00000676104.1 | NP_001361433.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0242 AC: 2199AN: 90888Hom.: 91 Cov.: 0 show subpopulations
GnomAD3 genomes
AF:
AC:
2199
AN:
90888
Hom.:
Cov.:
0
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD2 exomes AF: 0.0000680 AC: 5AN: 73502 AF XY: 0.0000700 show subpopulations
GnomAD2 exomes
AF:
AC:
5
AN:
73502
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
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Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00144 AC: 471AN: 327516Hom.: 11 Cov.: 0 AF XY: 0.00120 AC XY: 204AN XY: 170118 show subpopulations
GnomAD4 exome
AF:
AC:
471
AN:
327516
Hom.:
Cov.:
0
AF XY:
AC XY:
204
AN XY:
170118
show subpopulations
African (AFR)
AF:
AC:
323
AN:
9802
American (AMR)
AF:
AC:
27
AN:
12212
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
8890
East Asian (EAS)
AF:
AC:
1
AN:
14618
South Asian (SAS)
AF:
AC:
0
AN:
26598
European-Finnish (FIN)
AF:
AC:
0
AN:
22984
Middle Eastern (MID)
AF:
AC:
3
AN:
1618
European-Non Finnish (NFE)
AF:
AC:
37
AN:
215610
Other (OTH)
AF:
AC:
80
AN:
15184
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
22
43
65
86
108
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0242 AC: 2201AN: 90960Hom.: 92 Cov.: 0 AF XY: 0.0235 AC XY: 1011AN XY: 43032 show subpopulations
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
2201
AN:
90960
Hom.:
Cov.:
0
AF XY:
AC XY:
1011
AN XY:
43032
show subpopulations
African (AFR)
AF:
AC:
2060
AN:
26628
American (AMR)
AF:
AC:
81
AN:
7110
Ashkenazi Jewish (ASJ)
AF:
AC:
1
AN:
2228
East Asian (EAS)
AF:
AC:
0
AN:
3354
South Asian (SAS)
AF:
AC:
0
AN:
2032
European-Finnish (FIN)
AF:
AC:
0
AN:
5306
Middle Eastern (MID)
AF:
AC:
0
AN:
180
European-Non Finnish (NFE)
AF:
AC:
36
AN:
42440
Other (OTH)
AF:
AC:
23
AN:
1144
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
98
196
293
391
489
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
ClinVar
Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Benign:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
TMPRSS6-related disorder Benign:1
Jan 19, 2021
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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