22-37084757-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001374504.1(TMPRSS6):c.1056G>A(p.Ser352Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,564,542 control chromosomes in the GnomAD database, including 90,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9173 hom., cov: 32)

Exomes 𝑓: 0.34 ( 81511 hom. )

Consequence

TMPRSS6
NM_001374504.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -2.67

Publications

24 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 22-37084757-C-T is Benign according to our data. Variant chr22-37084757-C-T is described in ClinVar as Benign. ClinVar VariationId is 262719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.67 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 link	c.1056G>A	p.Ser352Ser	synonymous_variant	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.1056G>A	p.Ser352Ser	synonymous_variant	Exon 9 of 18		NM_001374504.1	ENSP00000501573.1

Frequencies

GnomAD3 genomes

AF:

0.343

AC:

52029

AN:

151832

Hom.:

9174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.382

Gnomad AMI

AF:

0.313

Gnomad AMR

AF:

0.247

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.327

Gnomad SAS

AF:

0.261

Gnomad FIN

AF:

0.410

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.342

Gnomad OTH

AF:

0.306

GnomAD2 exomes

AF:

0.312

AC:

55328

AN:

177408

AF XY:

0.311

show subpopulations

Gnomad AFR exome

AF:

0.369

Gnomad AMR exome

AF:

0.220

Gnomad ASJ exome

AF:

0.267

Gnomad EAS exome

AF:

0.320

Gnomad FIN exome

AF:

0.409

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.303

GnomAD4 exome

AF:

0.337

AC:

475763

AN:

1412592

Hom.:

81511

Cov.:

AF XY:

0.335

AC XY:

233597

AN XY:

697920

show subpopulations

African (AFR)

AF:

0.384

AC:

12497

AN:

32550

American (AMR)

AF:

0.220

AC:

8191

AN:

37174

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6740

AN:

25276

East Asian (EAS)

AF:

0.319

AC:

11925

AN:

37378

South Asian (SAS)

AF:

0.272

AC:

21841

AN:

80230

European-Finnish (FIN)

AF:

0.408

AC:

20428

AN:

50106

Middle Eastern (MID)

AF:

0.308

AC:

1569

AN:

5086

European-Non Finnish (NFE)

AF:

0.344

AC:

373366

AN:

1086204

Other (OTH)

AF:

0.328

AC:

19206

AN:

58588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

17044

34088

51133

68177

85221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12126

24252

36378

48504

60630

<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:

0.343

AC:

52046

AN:

151950

Hom.:

9173

Cov.:

AF XY:

0.344

AC XY:

25561

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.382

AC:

15821

AN:

41424

American (AMR)

AF:

0.246

AC:

3765

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

945

AN:

3472

East Asian (EAS)

AF:

0.328

AC:

1693

AN:

5162

South Asian (SAS)

AF:

0.261

AC:

1260

AN:

4826

European-Finnish (FIN)

AF:

0.410

AC:

4328

AN:

10556

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.342

AC:

23224

AN:

67912

Other (OTH)

AF:

0.302

AC:

638

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1765

3530

5295

7060

8825

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

506

1012

1518

2024

2530

<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:

0.338

Hom.:

35463

Bravo

AF:

0.334

Asia WGS

AF:

0.236

AC:

818

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcytic anemia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.48

(source)

DANN

Benign

0.85

PhyloP100

-2.7

PromoterAI

-0.013

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over