rs2235324

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001374504.1(TMPRSS6):c.730A>G(p.Lys244Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 1,611,216 control chromosomes in the GnomAD database, including 123,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12213 hom., cov: 33)

Exomes 𝑓: 0.39 ( 111170 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.74

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.389584E-4).

BP6

Variant 22-37089684-T-C is Benign according to our data. Variant chr22-37089684-T-C is described in ClinVar as [Benign]. Clinvar id is 262728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 linkuse as main transcript	c.730A>G	p.Lys244Glu	missense_variant	7/18	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.730A>G	p.Lys244Glu	missense_variant	7/18		NM_001374504.1	ENSP00000501573	P1	Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60430

AN:

151986

Hom.:

12211

Cov.:

show subpopulations

Gnomad AFR

AF:

0.433

Gnomad AMI

AF:

0.431

Gnomad AMR

AF:

0.364

Gnomad ASJ

AF:

0.329

Gnomad EAS

AF:

0.413

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.428

Gnomad MID

AF:

0.325

Gnomad NFE

AF:

0.384

Gnomad OTH

AF:

0.379

GnomAD3 exomes

AF:

0.382

AC:

93182

AN:

244230

Hom.:

17755

AF XY:

0.382

AC XY:

50610

AN XY:

132498

show subpopulations

Gnomad AFR exome

AF:

0.425

Gnomad AMR exome

AF:

0.321

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.403

Gnomad SAS exome

AF:

0.385

Gnomad FIN exome

AF:

0.426

Gnomad NFE exome

AF:

0.386

Gnomad OTH exome

AF:

0.378

GnomAD4 exome

AF:

0.389

AC:

567579

AN:

1459110

Hom.:

111170

Cov.:

AF XY:

0.389

AC XY:

281950

AN XY:

725612

show subpopulations

Gnomad4 AFR exome

AF:

0.435

Gnomad4 AMR exome

AF:

0.326

Gnomad4 ASJ exome

AF:

0.328

Gnomad4 EAS exome

AF:

0.443

Gnomad4 SAS exome

AF:

0.385

Gnomad4 FIN exome

AF:

0.426

Gnomad4 NFE exome

AF:

0.388

Gnomad4 OTH exome

AF:

0.388

GnomAD4 genome

AF:

0.397

AC:

60454

AN:

152106

Hom.:

12213

Cov.:

AF XY:

0.401

AC XY:

29783

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.432

Gnomad4 AMR

AF:

0.363

Gnomad4 ASJ

AF:

0.329

Gnomad4 EAS

AF:

0.414

Gnomad4 SAS

AF:

0.371

Gnomad4 FIN

AF:

0.428

Gnomad4 NFE

AF:

0.384

Gnomad4 OTH

AF:

0.374

Alfa

AF:

0.381

Hom.:

28506

Bravo

AF:

0.395

TwinsUK

AF:

0.396

AC:

1468

ALSPAC

AF:

0.380

AC:

1466

ESP6500AA

AF:

0.425

AC:

1871

ESP6500EA

AF:

0.381

AC:

3280

ExAC

AF:

0.383

AC:

46453

Asia WGS

AF:

0.349

AC:

1213

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Mar 06, 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. -

Iron-refractory iron deficiency anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.011

DANN

Benign

0.21

DEOGEN2

Benign

0.055

T;.;.;.;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.077

T;T;T;.;T

MetaRNN

Benign

0.00044

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

N;.;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.33

PROVEAN

Benign

0.14

N;N;N;N;N

REVEL

Benign

0.023

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.0

B;B;.;B;.

Vest4

0.050

MPC

0.22

ClinPred

0.015

GERP RS

-9.2

Varity_R

0.037

gMVP

0.50

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

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