NM_001374504.1:c.1842-6_1842-2dupCCCCA

Variant names:

• chr22-37069345-C-CTGGGG
• rs60484081
• NM_001374504.1:c.1842-6_1842-2dupCCCCA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 4P and 10B. PVS1_Strong BP6_Moderate BS1 BS2

The NM_001374504.1(TMPRSS6):​c.1842-6_1842-2dupCCCCA variant causes a splice acceptor, intron 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, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.94
• Publications: 2 publications found

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]

TMPRSS6 Gene-Disease associations (from GenCC):

• IRIDA syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11290992 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. GnomAdExome4 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 GnomAdExome4. There are 287 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1	c.1842-6_1842-2dupCCCCA		splice_acceptor_variant, intron_variant	Intron 15 of 17	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.1842-2_1842-1insCCCCA		splice_acceptor_variant, intron_variant	Intron 15 of 17		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 2639 AN: 90908 Hom.: 116 Cov.: 0

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

GnomAD2 exomes AF: 0.000150 AC: 11 AN: 73502 AF XY: 0.000163

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 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

African (AFR) AF: 0.0355 AC: 348 AN: 9792

American (AMR) AF: 0.00278 AC: 34 AN: 12212

Ashkenazi Jewish (ASJ) AF: 0.000112 AC: 1 AN: 8892

East Asian (EAS) AF: 0.0000684 AC: 1 AN: 14618

South Asian (SAS) AF: 0.000301 AC: 8 AN: 26598

European-Finnish (FIN) AF: 0.000305 AC: 7 AN: 22980

Middle Eastern (MID) AF: 0.00618 AC: 10 AN: 1618

European-Non Finnish (NFE) AF: 0.000450 AC: 97 AN: 215608

Other (OTH) AF: 0.00520 AC: 79 AN: 15182

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

African (AFR) AF: 0.0935 AC: 2490 AN: 26644

American (AMR) AF: 0.0141 AC: 100 AN: 7114

Ashkenazi Jewish (ASJ) AF: 0.000449 AC: 1 AN: 2228

East Asian (EAS) AF: 0.000894 AC: 3 AN: 3354

South Asian (SAS) AF: 0.00197 AC: 4 AN: 2028

European-Finnish (FIN) AF: 0.000188 AC: 1 AN: 5306

Middle Eastern (MID) AF: 0.0165 AC: 3 AN: 182

European-Non Finnish (NFE) AF: 0.000919 AC: 39 AN: 42442

Other (OTH) AF: 0.0166 AC: 19 AN: 1144

Alfa AF: 0.00 Hom.: 675

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.9
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs60484081; hg19: chr22-37465385;