22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS1

The NM_001374504.1(TMPRSS6):c.1842-11_1842-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.000318 in 418,402 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 Likely_benign. Variant got -2 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-CTGGGGTGGGG-C is Benign according to our data. Variant chr22-37069345-CTGGGGTGGGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 3054547.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000319 (29/91024) while in subpopulation AFR AF= 0.000637 (17/26688). AF 95% confidence interval is 0.000406. There are 1 homozygotes in gnomad4. There are 14 alleles in male gnomad4 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.1842-11_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.1842-11_1842-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001374504.1	P1

Frequencies

GnomAD3 genomes AF: 0.000297 AC: 27 AN: 90952 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000564

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000313 AC: 23 AN: 73502 Hom.: 0 AF XY: 0.000233 AC XY: 10 AN XY: 42836

Gnomad AFR exome AF: 0.000833

Gnomad AMR exome AF: 0.000142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000647

Gnomad FIN exome AF: 0.000120

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000318 AC: 104 AN: 327378 Hom.: 2 AF XY: 0.000347 AC XY: 59 AN XY: 170058

Gnomad4 AFR exome AF: 0.000408

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000685

Gnomad4 SAS exome AF: 0.000414

Gnomad4 FIN exome AF: 0.000218

Gnomad4 NFE exome AF: 0.000334

Gnomad4 OTH exome AF: 0.000527

GnomAD4 genome AF: 0.000319 AC: 29 AN: 91024 Hom.: 1 Cov.: 0 AF XY: 0.000325 AC XY: 14 AN XY: 43058

Gnomad4 AFR AF: 0.000637

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000283

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TMPRSS6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 13, 2021

This variant is classified as likely 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;