22-37069345-C-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant names:

• chr22-37069345-C-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG
• rs60484081
• NM_001374504.1:c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCACCCCACCCCA

Variant summary

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

The NM_001374504.1(TMPRSS6):​c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCACCCCACCCCA 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 0.000022 (0 hom., cov: 0)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• 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 syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

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	c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCACCCCACCCCA		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	c.1842-2_1842-1insCCCCACCCCACCCCACCCCACCCCACCCCACCCCA		splice_acceptor_variant, intron_variant	Intron 15 of 17		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.0000220 AC: 2 AN: 90956 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000752

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 Cov.: 0

GnomAD4 genome AF: 0.0000220 AC: 2 AN: 90956 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 42994

African (AFR) AF: 0.0000752 AC: 2 AN: 26598

American (AMR) AF: 0.00 AC: 0 AN: 7108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2228

East Asian (EAS) AF: 0.00 AC: 0 AN: 3364

South Asian (SAS) AF: 0.00 AC: 0 AN: 2042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 192

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 42444

Other (OTH) AF: 0.00 AC: 0 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

Other links and lift over

dbSNP: rs60484081; hg19: chr22-37465385;