22-37069345-CTGGGGTGGGGTGGGGTGGGG-CTGGGGTGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

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

• Frequency:
  • Genomes: 𝑓 0.014 (36 hom., cov: 0)
  • Exomes 𝑓: 0.0010 (6 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-CTGGGGTGGGGTGGGG is Benign according to our data. Variant chr22-37069345-C-CTGGGGTGGGGTGGGG is described in ClinVar as [Likely_benign]. Clinvar id is 707838.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 = 0.00104 (342/327514) while in subpopulation AFR AF= 0.0181 (177/9804). AF 95% confidence interval is 0.0159. There are 6 homozygotes in gnomad4_exome. There are 160 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_1842-1insCCCCACCCCACCCCA		splice_acceptor_variant		ENST00000676104.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1300 AN: 90934 Hom.: 36 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00914

Gnomad ASJ AF: 0.00583

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0208

Gnomad NFE AF: 0.000778

Gnomad OTH AF: 0.0141

GnomAD4 exome AF: 0.00104 AC: 342 AN: 327514 Hom.: 6 Cov.: 0 AF XY: 0.000941 AC XY: 160 AN XY: 170120

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000752

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000292

Gnomad4 OTH exome AF: 0.00283

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0144 AC: 1306 AN: 91006 Hom.: 36 Cov.: 0 AF XY: 0.0141 AC XY: 607 AN XY: 43050

Gnomad4 AFR AF: 0.0441

Gnomad4 AMR AF: 0.00914

Gnomad4 ASJ AF: 0.00583

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000778

Gnomad4 OTH AF: 0.0140

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 13, 2024

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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;