22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant names:

• chr22-37069345-C-CTGGGGTGGGGTGGGGTGGGG
• rs60484081
• NM_001374504.1:c.1842-21_1842-2dupCCCCACCCCACCCCACCCCA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS1

The NM_001374504.1(TMPRSS6):​c.1842-21_1842-2dupCCCCACCCCACCCCACCCCA 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. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (1 hom., cov: 0)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, 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 -1 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-CTGGGGTGGGGTGGGGTGGGG is Benign according to our data. Variant chr22-37069345-C-CTGGGGTGGGGTGGGGTGGGG is described in ClinVar as Likely_benign. ClinVar VariationId is 3054932.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000264 (24/91028) while in subpopulation AFR AF = 0.000862 (23/26688). AF 95% confidence interval is 0.000588. There are 1 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

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.1842-21_1842-2dupCCCCACCCCACCCCACCCCA		splice_acceptor intron	N/A	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1842-21_1842-2dupCCCCACCCCACCCCACCCCA		splice_acceptor intron	N/A	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1842-21_1842-2dupCCCCACCCCACCCCACCCCA		splice_acceptor 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.1842-2_1842-1insCCCCACCCCACCCCACCCCA		splice_acceptor intron	N/A	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1842-2_1842-1insCCCCACCCCACCCCACCCCA		splice_acceptor intron	N/A	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.1842-2_1842-1insCCCCACCCCACCCCACCCCA		splice_acceptor intron	N/A	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.000242 AC: 22 AN: 90956 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000790

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: 0.000880

GnomAD4 exome AF: 0.0000427 AC: 14 AN: 327526 Hom.: 0 Cov.: 0 AF XY: 0.0000294 AC XY: 5 AN XY: 170130

African (AFR) AF: 0.000408 AC: 4 AN: 9808

American (AMR) AF: 0.00 AC: 0 AN: 12212

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

East Asian (EAS) AF: 0.000205 AC: 3 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: 0.00 AC: 0 AN: 1618

European-Non Finnish (NFE) AF: 0.00000928 AC: 2 AN: 215612

Other (OTH) AF: 0.000329 AC: 5 AN: 15184

GnomAD4 genome AF: 0.000264 AC: 24 AN: 91028 Hom.: 1 Cov.: 0 AF XY: 0.000255 AC XY: 11 AN XY: 43058

African (AFR) AF: 0.000862 AC: 23 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: 0.00 AC: 0 AN: 42442

Other (OTH) AF: 0.000874 AC: 1 AN: 1144

Alfa AF: 0.00 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

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;