rs137853120

Positions:

chr22-37073553-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_001374504.1(TMPRSS6):c.1534G>A(p.Asp512Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,613,760 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D512G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.02

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-37073552-T-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 22-37073553-C-T is Pathogenic according to our data. Variant chr22-37073553-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-37073553-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 linkuse as main transcript	c.1534G>A	p.Asp512Asn	missense_variant	13/18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1 linkuse as main transcript	c.1534G>A	p.Asp512Asn	missense_variant	13/18		NM_001374504.1	ENSP00000501573	P1	Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251398

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000121

AC:

177

AN:

1461434

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000152

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Iron-refractory iron deficiency anemia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 24, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 28, 2009	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 25, 2023	The heterozygous p.Asp512Asn variant in TMPRSS6 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (hg38 chr22:g.37098319_37127846del), in one individual with iron-refractory iron deficiency anemia. This individual also carried a likely pathogenic variant (hg38 chr22:g.37098319_37127846del), however the phase of these variants are unknown at this time. The p.Asp512Asn variant in TMPRSS6 has been previously reported in 2 unrelated individuals with iron-refractory iron deficiency anemia (PMID: 19357398, PMID: 18408718) and segregated with disease in 2 affected individuals in one family (PMID: 18408718), but has been identified in 0.006% (8/129158) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs137853120). 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 variant has also been reported in ClinVar (Variation ID: 1404) and has been interpreted as pathogenic by OMIM and as likely pathogenic by Knight Diagnostic Laboratories, Oregon Health and Sciences University. Of the two unrelated individuals previously reported (PMID: 19357398, PMID: 18408718), one was a compound heterozygote that carried a reported pathogenic/likely pathogenic variant in trans (PMID: 18408718, ClinVar Variation ID: 1403) and the other was a compound heterozygote that carried a variant of uncertain significance in trans (PMID: 19357398, ClinVar Variation ID: 39759), which increases the likelihood that the p.Asp512Asn variant is pathogenic. The p.Asp512Asn variant is located in the LDLR domain, which may mediate interactions of the protein with macromolecules such as serine protease:inhibitor complexes and lipoproteins (PMID: 17981570), and multiple variants in the same region as p.Asp512Asn variant have been reported in association with disease in ClinVar (Variation ID: 30802, 1299579), suggesting that this variant is in a mutational hotspot and key functional domain and slightly supports pathogenicity. In vitro functional studies provide some evidence that the p.Asp512Asn variant may slightly impact protein function (PMID: 19357398). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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: PS3_Supporting, PM1_Supporting, PM2_Supporting, PM3, PP3 (Richards 2015). -

Microcytic anemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jun 01, 2017

- -

TMPRSS6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2024

The TMPRSS6 c.1561G>A variant is predicted to result in the amino acid substitution p.Asp521Asn. This variant has been reported in two compound heterozygous individuals with iron-refractory iron deficiency anemia (IRIDA) (Finberg et al. 2008. PubMed ID: 18408718; Silvestri et al. 2009. PubMed ID: 19357398). Functional studies have shown the c.1561G>A (p.Asp521Asn) variant to result in intracellular retention of the TMPRSS6 protein (Silvestri et al. 2009. PubMed ID: 19357398). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.64

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

H;.;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.8

D;D;D;D

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.058

T;T;T;T

Polyphen

1.0

D;D;.;D

Vest4

0.78

MVP

0.98

MPC

0.63

ClinPred

1.0

GERP RS

4.8

Varity_R

0.96

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over