22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PVS1_Strong BP6 BS1 BS2

The NM_001374504.1(TMPRSS6):​c.1842-11_1842-2delCCCCACCCCA variant causes a splice acceptor, splice region, intron change. The variant allele was found at a frequency of 0.000318 in 418,402 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 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-CTGGGGTGGGG-C is Benign according to our data. Variant chr22-37069345-CTGGGGTGGGG-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3054547.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000319 (29/91024) while in subpopulation AFR AF = 0.000637 (17/26688). AF 95% confidence interval is 0.000406. There are 1 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	NM_001374504.1	MANE Select	c.1842-11_1842-2delCCCCACCCCA		splice_acceptor splice_region intron	N/A	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1842-11_1842-2delCCCCACCCCA		splice_acceptor splice_region intron	N/A	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1842-11_1842-2delCCCCACCCCA		splice_acceptor splice_region intron	N/A	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS6	ENST00000676104.1	MANE Select	c.1842-11_1842-2delCCCCACCCCA		splice_acceptor splice_region intron	N/A	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1842-11_1842-2delCCCCACCCCA		splice_acceptor splice_region intron	N/A	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.1842-11_1842-2delCCCCACCCCA		splice_acceptor splice_region intron	N/A	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 27 AN: 90952 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000564

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: 0.000283

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000313 AC: 23 AN: 73502 AF XY: 0.000233

Gnomad AFR exome AF: 0.000833

Gnomad AMR exome AF: 0.000142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000120

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000318 AC: 104 AN: 327378 Hom.: 2 AF XY: 0.000347 AC XY: 59 AN XY: 170058

African (AFR) AF: 0.000408 AC: 4 AN: 9804

American (AMR) AF: 0.000246 AC: 3 AN: 12212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8892

East Asian (EAS) AF: 0.0000685 AC: 1 AN: 14606

South Asian (SAS) AF: 0.000414 AC: 11 AN: 26590

European-Finnish (FIN) AF: 0.000218 AC: 5 AN: 22970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1618

European-Non Finnish (NFE) AF: 0.000334 AC: 72 AN: 215512

Other (OTH) AF: 0.000527 AC: 8 AN: 15174

GnomAD4 genome AF: 0.000319 AC: 29 AN: 91024 Hom.: 1 Cov.: 0 AF XY: 0.000325 AC XY: 14 AN XY: 43058

African (AFR) AF: 0.000637 AC: 17 AN: 26688

American (AMR) AF: 0.00 AC: 0 AN: 7114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 182

European-Non Finnish (NFE) AF: 0.000283 AC: 12 AN: 42438

Other (OTH) AF: 0.00 AC: 0 AN: 1144

Alfa AF: 0.0000578 Hom.: 675

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TMPRSS6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=14/86	disease causing

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;