22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_StrongBP6_Very_StrongBS1BS2
The NM_001374504.1(TMPRSS6):c.1842-16_1842-2dupCCCCACCCCACCCCA variant causes a splice acceptor, intron change. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.014 ( 36 hom., cov: 0)
Exomes 𝑓: 0.0010 ( 6 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: Benign. The variant received -12 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-CTGGGGTGGGGTGGGG is Benign according to our data. Variant chr22-37069345-C-CTGGGGTGGGGTGGGG is described in ClinVar as [Likely_benign]. Clinvar id is 707838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00104 (342/327514) while in subpopulation AFR AF = 0.0181 (177/9804). AF 95% confidence interval is 0.0159. There are 6 homozygotes in GnomAdExome4. There are 160 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TMPRSS6 | NM_001374504.1 | c.1842-16_1842-2dupCCCCACCCCACCCCA | splice_acceptor_variant, intron_variant | Intron 15 of 17 | ENST00000676104.1 | NP_001361433.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0143 AC: 1300AN: 90934Hom.: 36 Cov.: 0 show subpopulations
GnomAD3 genomes
AF:
AC:
1300
AN:
90934
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:
GnomAD4 exome AF: 0.00104 AC: 342AN: 327514Hom.: 6 Cov.: 0 AF XY: 0.000941 AC XY: 160AN XY: 170120 show subpopulations
GnomAD4 exome
AF:
AC:
342
AN:
327514
Hom.:
Cov.:
0
AF XY:
AC XY:
160
AN XY:
170120
show subpopulations
African (AFR)
AF:
AC:
177
AN:
9804
American (AMR)
AF:
AC:
18
AN:
12212
Ashkenazi Jewish (ASJ)
AF:
AC:
29
AN:
8890
East Asian (EAS)
AF:
AC:
0
AN:
14618
South Asian (SAS)
AF:
AC:
2
AN:
26598
European-Finnish (FIN)
AF:
AC:
0
AN:
22984
Middle Eastern (MID)
AF:
AC:
10
AN:
1618
European-Non Finnish (NFE)
AF:
AC:
63
AN:
215606
Other (OTH)
AF:
AC:
43
AN:
15184
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
16
32
49
65
81
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: 0.0144 AC: 1306AN: 91006Hom.: 36 Cov.: 0 AF XY: 0.0141 AC XY: 607AN XY: 43050 show subpopulations
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1306
AN:
91006
Hom.:
Cov.:
0
AF XY:
AC XY:
607
AN XY:
43050
show subpopulations
African (AFR)
AF:
AC:
1175
AN:
26668
American (AMR)
AF:
AC:
65
AN:
7114
Ashkenazi Jewish (ASJ)
AF:
AC:
13
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:
4
AN:
182
European-Non Finnish (NFE)
AF:
AC:
33
AN:
42440
Other (OTH)
AF:
AC:
16
AN:
1144
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
56
111
167
222
278
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, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Jan 14, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Apr 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing
TMPRSS6: BS1 -
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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