22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS1

The NM_001374504.1(TMPRSS6):c.1842-16_1842-2del variant causes a splice acceptor, splice polypyrimidine tract, 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. 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_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.11249481 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. gnomad4_exome 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 gnomad4_exome. There are 118 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.1842-16_1842-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000676104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.1842-16_1842-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374504.1	P1

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

GnomAD3 exomes AF: 0.000177 AC: 13 AN: 73502 Hom.: 1 AF XY: 0.000187 AC XY: 8 AN XY: 42836

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 SAS exome AF: 0.000323

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

Gnomad4 AFR exome AF: 0.000102

Gnomad4 AMR exome AF: 0.0000820

Gnomad4 ASJ exome AF: 0.000225

Gnomad4 EAS exome AF: 0.000274

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000860

Gnomad4 OTH exome AF: 0.000857

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

Gnomad4 AFR AF: 0.000112

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000492

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs60484081; hg19: chr22-37465385;