22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGG

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.1842-2_1842-1insCCCCA variant causes a splice acceptor change. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (119 hom., cov: 0)
  • Exomes 𝑓: 0.0018 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMPRSS6 NM_001374504.1 splice_acceptor
• 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-C-CTGGGG is Benign according to our data. Variant chr22-37069345-C-CTGGGG is described in ClinVar as [Likely_benign]. Clinvar id is 780652.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00179 (585/327500) while in subpopulation AFR AF= 0.0355 (348/9792). AF 95% confidence interval is 0.0325. There are 13 homozygotes in gnomad4_exome. There are 287 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_1842-1insCCCCA		splice_acceptor_variant		ENST00000676104.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2639 AN: 90908 Hom.: 116 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0929

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.000449

Gnomad EAS AF: 0.000892

Gnomad SAS AF: 0.00245

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0156

Gnomad NFE AF: 0.000919

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.000150 AC: 11 AN: 73502 Hom.: 0 AF XY: 0.000163 AC XY: 7 AN XY: 42836

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.000284

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: 0.00179 AC: 585 AN: 327500 Hom.: 13 Cov.: 0 AF XY: 0.00169 AC XY: 287 AN XY: 170110

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.00278

Gnomad4 ASJ exome AF: 0.000112

Gnomad4 EAS exome AF: 0.0000684

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.000305

Gnomad4 NFE exome AF: 0.000450

Gnomad4 OTH exome AF: 0.00520

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0292 AC: 2660 AN: 90980 Hom.: 119 Cov.: 0 AF XY: 0.0299 AC XY: 1288 AN XY: 43036

Gnomad4 AFR AF: 0.0935

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.000449

Gnomad4 EAS AF: 0.000894

Gnomad4 SAS AF: 0.00197

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000919

Gnomad4 OTH AF: 0.0166

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 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;