22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGG

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BS1 BS2

The NM_001374504.1(TMPRSS6):​c.1842-16_1842-2delCCCCACCCCACCCCA variant causes a splice acceptor, splice region, intron change. The variant allele was found at a frequency of 0.000581 in 418,010 control chromosomes in the GnomAD database, including 12 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00071 (12 hom.)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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 -4 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 4, offset of 0 (no position change), new splice context is: ctcaccccaccccaccccAGcat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000713 (233/326996) while in subpopulation MID AF = 0.00185 (3/1618). AF 95% confidence interval is 0.000758. There are 12 homozygotes in GnomAdExome4. There are 118 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.1842-16_1842-2delCCCCACCCCACCCCA		splice_acceptor_variant, splice_region_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.1842-16_1842-2delCCCCACCCCACCCCA		splice_acceptor_variant, splice_region_variant, intron_variant	Intron 15 of 17		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.000110 AC: 10 AN: 90942 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000490

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00521

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000177 AC: 13 AN: 73502 AF XY: 0.000187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000254

Gnomad EAS exome AF: 0.000600

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.000605

GnomAD4 exome AF: 0.000713 AC: 233 AN: 326996 Hom.: 12 AF XY: 0.000695 AC XY: 118 AN XY: 169850

African (AFR) AF: 0.000102 AC: 1 AN: 9802

American (AMR) AF: 0.0000820 AC: 1 AN: 12200

Ashkenazi Jewish (ASJ) AF: 0.000225 AC: 2 AN: 8882

East Asian (EAS) AF: 0.000274 AC: 4 AN: 14614

South Asian (SAS) AF: 0.000904 AC: 24 AN: 26558

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22976

Middle Eastern (MID) AF: 0.00185 AC: 3 AN: 1618

European-Non Finnish (NFE) AF: 0.000860 AC: 185 AN: 215176

Other (OTH) AF: 0.000857 AC: 13 AN: 15170

GnomAD4 genome AF: 0.000110 AC: 10 AN: 91014 Hom.: 0 Cov.: 0 AF XY: 0.0000929 AC XY: 4 AN XY: 43044

African (AFR) AF: 0.000112 AC: 3 AN: 26688

American (AMR) AF: 0.00 AC: 0 AN: 7112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2228

East Asian (EAS) AF: 0.00 AC: 0 AN: 3354

South Asian (SAS) AF: 0.000492 AC: 1 AN: 2032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5304

Middle Eastern (MID) AF: 0.00549 AC: 1 AN: 182

European-Non Finnish (NFE) AF: 0.000118 AC: 5 AN: 42436

Other (OTH) AF: 0.00 AC: 0 AN: 1142

Alfa AF: 0.000231 Hom.: 675

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=94/6	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;