22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant names:

• chr22-37069345-C-CTGGGGTGGGGTGGGG
• rs60484081
• NM_001374504.1:c.1842-16_1842-2dupCCCCACCCCACCCCA

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BS1 BS2

The NM_001374504.1(TMPRSS6):​c.1842-16_1842-2dupCCCCACCCCACCCCA 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 0)
  • Exomes 𝑓: 0.0010 (6 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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: 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-C-CTGGGGTGGGGTGGGG is Benign according to our data. Variant chr22-37069345-C-CTGGGGTGGGGTGGGG is described in ClinVar as Likely_benign. ClinVar VariationId is 707838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00104 (342/327514) while in subpopulation AFR AF = 0.0181 (177/9804). AF 95% confidence interval is 0.0159. There are 6 homozygotes in GnomAdExome4. There are 160 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1842-16_1842-2dupCCCCACCCCACCCCA		splice_acceptor intron	N/A	NP_001361433.1	Q8IU80-1
	TMPRSS6	NM_001289000.2		c.1842-16_1842-2dupCCCCACCCCACCCCA		splice_acceptor intron	N/A	NP_001275929.1	Q8IU80-5
	TMPRSS6	NM_001289001.2		c.1842-16_1842-2dupCCCCACCCCACCCCA		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_1842-1insCCCCACCCCACCCCA		splice_acceptor intron	N/A	ENSP00000501573.1	Q8IU80-1
	TMPRSS6	ENST00000406856.7	TSL:1	c.1842-2_1842-1insCCCCACCCCACCCCA		splice_acceptor intron	N/A	ENSP00000384964.1	Q8IU80-5
	TMPRSS6	ENST00000346753.9	TSL:1	c.1842-2_1842-1insCCCCACCCCACCCCA		splice_acceptor intron	N/A	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 1300 AN: 90934 Hom.: 36 Cov.: 0

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00914

Gnomad ASJ AF: 0.00583

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0208

Gnomad NFE AF: 0.000778

Gnomad OTH AF: 0.0141

GnomAD4 exome AF: 0.00104 AC: 342 AN: 327514 Hom.: 6 Cov.: 0 AF XY: 0.000941 AC XY: 160 AN XY: 170120

African (AFR) AF: 0.0181 AC: 177 AN: 9804

American (AMR) AF: 0.00147 AC: 18 AN: 12212

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 29 AN: 8890

East Asian (EAS) AF: 0.00 AC: 0 AN: 14618

South Asian (SAS) AF: 0.0000752 AC: 2 AN: 26598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22984

Middle Eastern (MID) AF: 0.00618 AC: 10 AN: 1618

European-Non Finnish (NFE) AF: 0.000292 AC: 63 AN: 215606

Other (OTH) AF: 0.00283 AC: 43 AN: 15184

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0144 AC: 1306 AN: 91006 Hom.: 36 Cov.: 0 AF XY: 0.0141 AC XY: 607 AN XY: 43050

African (AFR) AF: 0.0441 AC: 1175 AN: 26668

American (AMR) AF: 0.00914 AC: 65 AN: 7114

Ashkenazi Jewish (ASJ) AF: 0.00583 AC: 13 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: 0.0220 AC: 4 AN: 182

European-Non Finnish (NFE) AF: 0.000778 AC: 33 AN: 42440

Other (OTH) AF: 0.0140 AC: 16 AN: 1144

Alfa AF: 0.00 Hom.: 675

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;