22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant names:

• chr22-37069345-C-CTGGGGTGGGG
• rs60484081
• NM_001374504.1:c.1842-11_1842-2dupCCCCACCCCA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• 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: 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
TMPRSS6	NM_001374504.1	c.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
TMPRSS6	ENST00000676104.1	c.1842-2_1842-1insCCCCACCCCA		splice_acceptor_variant, intron_variant	Intron 15 of 17		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 2199 AN: 90888 Hom.: 91 Cov.: 0

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

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

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

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

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

Alfa AF: 0.00 Hom.: 675

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

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

Other links and lift over

dbSNP: rs60484081; hg19: chr22-37465385;