22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGG

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PVS1_Strong BP6_Very_Strong BA1

The NM_001374504.1(TMPRSS6):c.1842-6_1842-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.358 in 416,978 control chromosomes in the GnomAD database, including 28,314 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (8919 hom., cov: 0)
  • Exomes 𝑓: 0.32 (19395 hom.)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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 -12 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-CTGGGG-C is Benign according to our data. Variant chr22-37069345-CTGGGG-C is described in ClinVar as [Benign]. Clinvar id is 262724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.1842-6_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.1842-6_1842-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374504.1	P1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 46241 AN: 90652 Hom.: 8915 Cov.: 0

Gnomad AFR AF: 0.525

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.536

Gnomad NFE AF: 0.501

Gnomad OTH AF: 0.502

GnomAD3 exomes AF: 0.220 AC: 16145 AN: 73502 Hom.: 2957 AF XY: 0.216 AC XY: 9238 AN XY: 42836

Gnomad AFR exome AF: 0.287

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.230

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.211

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.316 AC: 102986 AN: 326256 Hom.: 19395 AF XY: 0.322 AC XY: 54514 AN XY: 169448

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.232

Gnomad4 ASJ exome AF: 0.401

Gnomad4 EAS exome AF: 0.558

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.431

Gnomad4 NFE exome AF: 0.284

Gnomad4 OTH exome AF: 0.382

GnomAD4 genome AF: 0.510 AC: 46265 AN: 90722 Hom.: 8919 Cov.: 0 AF XY: 0.509 AC XY: 21831 AN XY: 42930

Gnomad4 AFR AF: 0.524

Gnomad4 AMR AF: 0.461

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.405

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.501

Gnomad4 OTH AF: 0.499

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 3449/7484=46.08% -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Microcytic anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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;