rs137853121

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001374504.1(TMPRSS6):c.1038C>A(p.Tyr346*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000051 in 1,567,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

TMPRSS6
NM_001374504.1 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.66

Publications

2 publications found

Variant links:

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

TMPRSS6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-37084775-G-T is Pathogenic according to our data. Variant chr22-37084775-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 link	c.1038C>A	p.Tyr346*	stop_gained	Exon 9 of 18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1 link	c.1038C>A	p.Tyr346*	stop_gained	Exon 9 of 18		NM_001374504.1	ENSP00000501573.1		Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000560

AC:

AN:

178518

AF XY:

0.0000106

show subpopulations

Gnomad AFR exome

AF:

0.0000934

Gnomad AMR exome

AF:

0.00

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:

0.00000424

AC:

AN:

1414890

Hom.:

Cov.:

AF XY:

0.00000572

AC XY:

AN XY:

699108

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32638

American (AMR)

AF:

0.00

AC:

AN:

37436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25278

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37490

South Asian (SAS)

AF:

0.00

AC:

AN:

80376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50206

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5426

European-Non Finnish (NFE)

AF:

0.00000368

AC:

AN:

1087368

Other (OTH)

AF:

0.00

AC:

AN:

58672

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74474

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41554

American (AMR)

AF:

0.0000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.038550), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Iron-refractory iron deficiency anemia

Pathogenic:2

May 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The heterozygous p.Tyr346Ter variant in TMPRSS6 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (Variation ID: 1406), in one individual with iron-refractory iron deficiency anemia. This individual also carried a likely pathogenic variant (Variation ID: 1406), however the phase of these variants is unknown at this time. The p.Tyr346Ter variant in TMPRSS6 has been previously reported in one individual with iron-refractory iron deficiency anemia (PMID: 18408718) but has been identified in 0.009% (1/10706) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137853121). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This previously reported individual was a compound heterozygote that carried a reported likely pathogenic variant in unknown phase (ClinVar Variation ID: 1406), which increases the likelihood that the p.Tyr346Ter variant is pathogenic.This variant has also been reported in ClinVar (Variation ID: 1405) and has been interpreted as pathogenic by OMIM and as likely pathogenic by GeneDx. This nonsense variant leads to a premature termination codon at position 346, which is predicted to lead to a truncated or absent protein. Loss of function of the TMPRSS6 gene is an established disease mechanism in autosomal recessive iron-refractory iron deficiency anemia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive iron-refractory iron deficiency anemia. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015). -

not provided

Pathogenic:1

Jul 08, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a second variant (phase unknown) in an individual with iron-refractory iron deficiency anemia in the literature (PMID: 18408718); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 25156943, 18408718) -

TMPRSS6-related disorder

Pathogenic:1

Nov 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TMPRSS6 c.1065C>A variant is predicted to result in premature protein termination (p.Tyr355*). This variant was reported along with a second likely disease-causing TMPRSS6 variant in an individual with iron-refractory iron deficiency anaemia (Finberg KE et al 2008. PubMed ID: 18408718). This variant is reported in 0.0093% of alleles in individuals of African descent in gnomAD. Nonsense variants in TMPRSS6 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.38

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.90

PhyloP100

1.7

Vest4

0.81

GERP RS

3.5

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

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

Publications

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rs137853121

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over