22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PVS1_Strong BP6_Very_Strong BS1

The NM_001374504.1(TMPRSS6):c.1842-2_1842-1insCCCCACCCCA variant causes a splice acceptor change. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (92 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (11 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -8 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 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-CTGGGGTGGGG is Benign according to our data. Variant chr22-37069345-C-CTGGGGTGGGG is described in ClinVar as [Likely_benign]. Clinvar id is 786381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00144 (471/327516) while in subpopulation AFR AF= 0.033 (323/9802). AF 95% confidence interval is 0.03. There are 11 homozygotes in gnomad4_exome. There are 204 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.1842-2_1842-1insCCCCACCCCA		splice_acceptor_variant		ENST00000676104.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2199 AN: 90888 Hom.: 91 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.000449

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0105

Gnomad NFE AF: 0.000848

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.0000680 AC: 5 AN: 73502 Hom.: 0 AF XY: 0.0000700 AC XY: 3 AN XY: 42836

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00144 AC: 471 AN: 327516 Hom.: 11 Cov.: 0 AF XY: 0.00120 AC XY: 204 AN XY: 170118

Gnomad4 AFR exome AF: 0.0330

Gnomad4 AMR exome AF: 0.00221

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000684

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000172

Gnomad4 OTH exome AF: 0.00527

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0242 AC: 2201 AN: 90960 Hom.: 92 Cov.: 0 AF XY: 0.0235 AC XY: 1011 AN XY: 43032

Gnomad4 AFR AF: 0.0774

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.000449

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000848

Gnomad4 OTH AF: 0.0201

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 25, 2023

- -

TMPRSS6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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;