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

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts 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: 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
TMPRSS6NM_001374504.1 linkc.1842-16_1842-2dupCCCCACCCCACCCCA 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_1842-1insCCCCACCCCACCCCA splice_acceptor_variant, intron_variant Intron 15 of 17 NM_001374504.1 ENSP00000501573.1 Q8IU80-1

Frequencies

GnomAD3 genomes
AF:
0.0143
AC:
1300
AN:
90934
Hom.:
36
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.0440
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00914
Gnomad ASJ
AF:
0.00583
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0208
Gnomad NFE
AF:
0.000778
Gnomad OTH
AF:
0.0141
GnomAD4 exome
AF:
0.00104
AC:
342
AN:
327514
Hom.:
6
Cov.:
0
AF XY:
0.000941
AC XY:
160
AN XY:
170120
show subpopulations
African (AFR)
AF:
0.0181
AC:
177
AN:
9804
American (AMR)
AF:
0.00147
AC:
18
AN:
12212
Ashkenazi Jewish (ASJ)
AF:
0.00326
AC:
29
AN:
8890
East Asian (EAS)
AF:
0.00
AC:
0
AN:
14618
South Asian (SAS)
AF:
0.0000752
AC:
2
AN:
26598
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
22984
Middle Eastern (MID)
AF:
0.00618
AC:
10
AN:
1618
European-Non Finnish (NFE)
AF:
0.000292
AC:
63
AN:
215606
Other (OTH)
AF:
0.00283
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

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:
0.0144
AC:
1306
AN:
91006
Hom.:
36
Cov.:
0
AF XY:
0.0141
AC XY:
607
AN XY:
43050
show subpopulations
African (AFR)
AF:
0.0441
AC:
1175
AN:
26668
American (AMR)
AF:
0.00914
AC:
65
AN:
7114
Ashkenazi Jewish (ASJ)
AF:
0.00583
AC:
13
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:
0.0220
AC:
4
AN:
182
European-Non Finnish (NFE)
AF:
0.000778
AC:
33
AN:
42440
Other (OTH)
AF:
0.0140
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

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
20
40
60
80
100
<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, 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: 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