Genetic Variant NM_001374504.1:c.1842-21_1842-2delCCCCACCCCACCCCACCCCA (chr22-37069345-CTGGGGTGGGGTGGGGTGGGG-C) – 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.1842-21_1842-2delCCCCACCCCACCCCACCCCA variant causes a splice acceptor, splice region, intron change. The variant allele was found at a frequency of 0.0000502 in 418,128 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000011 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

TMPRSS6
NM_001374504.1 splice_acceptor, splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U: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

TMPRSS6 links:

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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 3.9, offset of 0 (no position change), new splice context is: ctcacctcaccccaccccAGcat. 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.1842-21_1842-2delCCCCACCCCACCCCACCCCA		splice_acceptor_variant, splice_region_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.1842-21_1842-2delCCCCACCCCACCCCACCCCA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 15 of 17		NM_001374504.1	ENSP00000501573.1		Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.0000110

AC:

AN:

90948

Hom.:

Cov.:

show subpopulations

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:

0.000490

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000408

AC:

AN:

73502

AF XY:

0.0000700

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000611

AC:

AN:

327108

Hom.:

AF XY:

0.0000765

AC XY:

AN XY:

169942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9804

American (AMR)

AF:

0.00

AC:

AN:

12212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8888

East Asian (EAS)

AF:

0.0000684

AC:

AN:

14614

South Asian (SAS)

AF:

0.000263

AC:

AN:

26586

European-Finnish (FIN)

AF:

0.0000435

AC:

AN:

22982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1616

European-Non Finnish (NFE)

AF:

0.0000511

AC:

AN:

215234

Other (OTH)

AF:

0.00

AC:

AN:

15172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000110

AC:

AN:

91020

Hom.:

Cov.:

AF XY:

0.0000232

AC XY:

AN XY:

43052

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26686

American (AMR)

AF:

0.00

AC:

AN:

7112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2228

East Asian (EAS)

AF:

0.00

AC:

AN:

3354

South Asian (SAS)

AF:

0.000492

AC:

AN:

2032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

182

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

42438

Other (OTH)

AF:

0.00

AC:

AN:

1144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

675

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 17, 2022

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Iron-refractory iron deficiency anemia

Uncertain:1

Jun 18, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.9

Mutation Taster

=25/75

disease causing (long InDel)

(source)

Splicing

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

Publications

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NM_001374504.1:c.1842-21_1842-2delCCCCACCCCACCCCACCCCA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over