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

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 5.94

Publications

2 publications found
Variant links:
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 syndrome
    Inheritance: 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
TMPRSS6NM_001374504.1 linkc.1842-11_1842-2dupCCCCACCCCA splice_acceptor_variant, intron_variant Intron 15 of 17 ENST00000676104.1 NP_001361433.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMPRSS6ENST00000676104.1 linkc.1842-2_1842-1insCCCCACCCCA splice_acceptor_variant, intron_variant Intron 15 of 17 NM_001374504.1 ENSP00000501573.1 Q8IU80-1

Frequencies

GnomAD3 genomes
AF:
0.0242
AC:
2199
AN:
90888
Hom.:
91
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.0775
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0114
Gnomad ASJ
AF:
0.000449
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0105
Gnomad NFE
AF:
0.000848
Gnomad OTH
AF:
0.0202
GnomAD2 exomes
AF:
0.0000680
AC:
5
AN:
73502
AF XY:
0.0000700
show subpopulations
Gnomad AFR exome
AF:
0.00208
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00144
AC:
471
AN:
327516
Hom.:
11
Cov.:
0
AF XY:
0.00120
AC XY:
204
AN XY:
170118
show subpopulations
African (AFR)
AF:
0.0330
AC:
323
AN:
9802
American (AMR)
AF:
0.00221
AC:
27
AN:
12212
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
8890
East Asian (EAS)
AF:
0.0000684
AC:
1
AN:
14618
South Asian (SAS)
AF:
0.00
AC:
0
AN:
26598
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
22984
Middle Eastern (MID)
AF:
0.00185
AC:
3
AN:
1618
European-Non Finnish (NFE)
AF:
0.000172
AC:
37
AN:
215610
Other (OTH)
AF:
0.00527
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

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0242
AC:
2201
AN:
90960
Hom.:
92
Cov.:
0
AF XY:
0.0235
AC XY:
1011
AN XY:
43032
show subpopulations
African (AFR)
AF:
0.0774
AC:
2060
AN:
26628
American (AMR)
AF:
0.0114
AC:
81
AN:
7110
Ashkenazi Jewish (ASJ)
AF:
0.000449
AC:
1
AN:
2228
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3354
South Asian (SAS)
AF:
0.00
AC:
0
AN:
2032
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
5306
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
180
European-Non Finnish (NFE)
AF:
0.000848
AC:
36
AN:
42440
Other (OTH)
AF:
0.0201
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

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
26
52
78
104
130
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
675

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
5.9
Mutation Taster
=99/1
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs60484081; hg19: chr22-37465385; API