rs115270691

chr22-37103525-G-Achr22-37103525-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000346753.9(TMPRSS6):c.-13C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0265 in 1,614,108 control chromosomes in the GnomAD database, including 634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (64 hom., cov: 32)
  • Exomes 𝑓: 0.027 (570 hom.)
• Consequence: TMPRSS6 ENST00000346753.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.37

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-37103525-G-A is Benign according to our data. Variant chr22-37103525-G-A is described in ClinVar as [Benign]. Clinvar id is 262723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS6	NM_001374504.1	c.-1-107C>T		intron_variant		ENST00000676104.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS6	ENST00000676104.1	c.-1-107C>T		intron_variant			NM_001374504.1	P1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3744 AN: 152198 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0288

Gnomad OTH AF: 0.0401

GnomAD3 exomes AF: 0.0212 AC: 5337 AN: 251246 Hom.: 80 AF XY: 0.0214 AC XY: 2908 AN XY: 135828

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.00646

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0269

GnomAD4 exome AF: 0.0267 AC: 38976 AN: 1461792 Hom.: 570 Cov.: 34 AF XY: 0.0263 AC XY: 19137 AN XY: 727198

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.00622

Gnomad4 NFE exome AF: 0.0297

Gnomad4 OTH exome AF: 0.0296

GnomAD4 genome AF: 0.0245 AC: 3739 AN: 152316 Hom.: 64 Cov.: 32 AF XY: 0.0230 AC XY: 1717 AN XY: 74492

Gnomad4 AFR AF: 0.0241

Gnomad4 AMR AF: 0.0308

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.00433

Gnomad4 NFE AF: 0.0287

Gnomad4 OTH AF: 0.0392

Alfa AF: 0.0224 Hom.: 31

Bravo AF: 0.0271

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0323

EpiControl AF: 0.0318

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

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

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	4.4
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs115270691; hg19: chr22-37499565;