Genetic Variant TMPRSS6:c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA (chr22-37069345-C-CTGGGGTGGGGTGGGGTGGGGTGGGG) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001374504.1(TMPRSS6):c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMPRSS6
NM_001374504.1 splice_acceptor, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.94

Publications

0 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

TMPRSS6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 link	c.1842-26_1842-2dupCCCCACCCCACCCCACCCCACCCCA		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
TMPRSS6	ENST00000676104.1 link	c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCA		splice_acceptor_variant, intron_variant	Intron 15 of 17		NM_001374504.1	ENSP00000501573.1		Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

90956

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000916

AC:

AN:

327528

Hom.:

Cov.:

AF XY:

0.00000588

AC XY:

AN XY:

170130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9810

American (AMR)

AF:

0.00

AC:

AN:

12212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8892

East Asian (EAS)

AF:

0.00

AC:

AN:

14618

South Asian (SAS)

AF:

0.00

AC:

AN:

26598

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1618

European-Non Finnish (NFE)

AF:

0.0000139

AC:

AN:

215612

Other (OTH)

AF:

0.00

AC:

AN:

15184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

90956

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

42994

African (AFR)

AF:

0.00

AC:

AN:

26598

American (AMR)

AF:

0.00

AC:

AN:

7108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2228

East Asian (EAS)

AF:

0.00

AC:

AN:

3364

South Asian (SAS)

AF:

0.00

AC:

AN:

2042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

42444

Other (OTH)

AF:

0.00

AC:

AN:

1136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.9

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over