chr22-37069345-CTGGGG-C

Variant names:

• chr22-37069345-CTGGGG-C
• rs60484081
• NM_001374504.1:c.1842-6_1842-2delCCCCA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001374504.1(TMPRSS6):​c.1842-6_1842-2delCCCCA variant causes a splice acceptor, splice region, intron change. The variant allele was found at a frequency of 0.358 in 416,978 control chromosomes in the GnomAD database, including 28,314 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (8919 hom., cov: 0)
  • Exomes 𝑓: 0.32 (19395 hom.)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: 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-CTGGGG-C is Benign according to our data. Variant chr22-37069345-CTGGGG-C is described in ClinVar as Benign. ClinVar VariationId is 262724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374504.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	NM_001374504.1	MANE Select	c.1842-6_1842-2delCCCCA		splice_acceptor splice_region intron	N/A	NP_001361433.1
	TMPRSS6	NM_001289000.2		c.1842-6_1842-2delCCCCA		splice_acceptor splice_region intron	N/A	NP_001275929.1
	TMPRSS6	NM_001289001.2		c.1842-6_1842-2delCCCCA		splice_acceptor splice_region intron	N/A	NP_001275930.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.1842-6_1842-2delCCCCA		splice_acceptor splice_region intron	N/A	ENSP00000501573.1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1842-6_1842-2delCCCCA		splice_acceptor splice_region intron	N/A	ENSP00000384964.1
	TMPRSS6	ENST00000346753.9	TSL:1	c.1842-6_1842-2delCCCCA		splice_acceptor splice_region intron	N/A	ENSP00000334962.6

Frequencies

GnomAD3 genomes AF: 0.510 AC: 46241 AN: 90652 Hom.: 8915 Cov.: 0

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.536

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.502

GnomAD2 exomes AF: 0.220 AC: 16145 AN: 73502 AF XY: 0.216

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.316 AC: 102986 AN: 326256 Hom.: 19395 AF XY: 0.322 AC XY: 54514 AN XY: 169448

African (AFR) AF: 0.285 AC: 2789 AN: 9786

American (AMR) AF: 0.232 AC: 2820 AN: 12174

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 3545 AN: 8850

East Asian (EAS) AF: 0.558 AC: 8106 AN: 14528

South Asian (SAS) AF: 0.328 AC: 8685 AN: 26452

European-Finnish (FIN) AF: 0.431 AC: 9861 AN: 22898

Middle Eastern (MID) AF: 0.298 AC: 479 AN: 1608

European-Non Finnish (NFE) AF: 0.284 AC: 60931 AN: 214842

Other (OTH) AF: 0.382 AC: 5770 AN: 15118

GnomAD4 genome AF: 0.510 AC: 46265 AN: 90722 Hom.: 8919 Cov.: 0 AF XY: 0.509 AC XY: 21831 AN XY: 42930

African (AFR) AF: 0.524 AC: 13954 AN: 26610

American (AMR) AF: 0.461 AC: 3269 AN: 7094

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1132 AN: 2222

East Asian (EAS) AF: 0.551 AC: 1841 AN: 3344

South Asian (SAS) AF: 0.405 AC: 820 AN: 2024

European-Finnish (FIN) AF: 0.591 AC: 3124 AN: 5284

Middle Eastern (MID) AF: 0.544 AC: 99 AN: 182

European-Non Finnish (NFE) AF: 0.501 AC: 21180 AN: 42284

Other (OTH) AF: 0.499 AC: 571 AN: 1144

Alfa AF: 0.192 Hom.: 675

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 3449/7484=46.08%

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Microcytic anemia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=96/4	polymorphism (auto)

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; COSMIC: COSV60977486;