chr22-37089684-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

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

Publications

51 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: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374504.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMPRSS6	NM_001374504.1	MANE Select	c.730A>G	p.Lys244Glu	missense	Exon 7 of 18	NP_001361433.1
TMPRSS6	NM_001289000.2		c.730A>G	p.Lys244Glu	missense	Exon 7 of 19	NP_001275929.1
TMPRSS6	NM_001289001.2		c.730A>G	p.Lys244Glu	missense	Exon 7 of 18	NP_001275930.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMPRSS6	ENST00000676104.1	MANE Select	c.730A>G	p.Lys244Glu	missense	Exon 7 of 18	ENSP00000501573.1
TMPRSS6	ENST00000406856.7	TSL:1	c.730A>G	p.Lys244Glu	missense	Exon 7 of 19	ENSP00000384964.1
TMPRSS6	ENST00000346753.9	TSL:1	c.730A>G	p.Lys244Glu	missense	Exon 7 of 18	ENSP00000334962.6

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

GnomAD2 exomes

AF:

0.382

AC:

93182

AN:

244230

AF XY:

0.382

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 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

African (AFR)

AF:

0.435

AC:

14549

AN:

33446

American (AMR)

AF:

0.326

AC:

14455

AN:

44408

Ashkenazi Jewish (ASJ)

AF:

0.328

AC:

8549

AN:

26064

East Asian (EAS)

AF:

0.443

AC:

17569

AN:

39622

South Asian (SAS)

AF:

0.385

AC:

33015

AN:

85792

European-Finnish (FIN)

AF:

0.426

AC:

22534

AN:

52900

Middle Eastern (MID)

AF:

0.386

AC:

2201

AN:

5708

European-Non Finnish (NFE)

AF:

0.388

AC:

431323

AN:

1110904

Other (OTH)

AF:

0.388

AC:

23384

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

21902

43804

65706

87608

109510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13596

27192

40788

54384

67980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.397

AC:

60454

AN:

152106

Hom.:

12213

Cov.:

AF XY:

0.401

AC XY:

29783

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.432

AC:

17932

AN:

41488

American (AMR)

AF:

0.363

AC:

5554

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.329

AC:

1140

AN:

3464

East Asian (EAS)

AF:

0.414

AC:

2141

AN:

5170

South Asian (SAS)

AF:

0.371

AC:

1786

AN:

4820

European-Finnish (FIN)

AF:

0.428

AC:

4531

AN:

10580

Middle Eastern (MID)

AF:

0.332

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.384

AC:

26090

AN:

67986

Other (OTH)

AF:

0.374

AC:

791

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1920

3840

5759

7679

9599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.385

Hom.:

39624

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Iron-refractory iron deficiency anemia (1)

Microcytic anemia (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.011

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.055

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.077

MetaRNN

Benign

0.00044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

PhyloP100

-1.7

PrimateAI

Benign

0.33

PROVEAN

Benign

0.14

REVEL

Benign

0.023

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.050

MPC

0.22

ClinPred

0.015

GERP RS

-9.2

Varity_R

0.037

gMVP

0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over