dbSNP rs117576908: TMPRSS6:p.Arg437Trp (chr22-37075168-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001374504.1(TMPRSS6):c.1309C>T(p.Arg437Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,614,034 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R437Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0080 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0077 ( 136 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.32

Publications

11 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, PanelApp Australia, Orphanet

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=0.005034983).

BP6

Variant 22-37075168-G-A is Benign according to our data. Variant chr22-37075168-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00799 (1217/152320) while in subpopulation NFE AF = 0.00681 (463/68020). AF 95% confidence interval is 0.00629. There are 25 homozygotes in GnomAd4. There are 769 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

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	UniProt
TMPRSS6	NM_001374504.1	MANE Select	c.1309C>T	p.Arg437Trp	missense	Exon 11 of 18	NP_001361433.1	Q8IU80-1
TMPRSS6	NM_001289000.2		c.1309C>T	p.Arg437Trp	missense	Exon 11 of 19	NP_001275929.1	Q8IU80-5
TMPRSS6	NM_001289001.2		c.1309C>T	p.Arg437Trp	missense	Exon 11 of 18	NP_001275930.1	Q8IU80-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMPRSS6	ENST00000676104.1	MANE Select	c.1309C>T	p.Arg437Trp	missense	Exon 11 of 18	ENSP00000501573.1	Q8IU80-1
TMPRSS6	ENST00000406856.7	TSL:1	c.1309C>T	p.Arg437Trp	missense	Exon 11 of 19	ENSP00000384964.1	Q8IU80-5
TMPRSS6	ENST00000346753.9	TSL:1	c.1309C>T	p.Arg437Trp	missense	Exon 11 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.00800

AC:

1217

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0596

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00681

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00950

AC:

2387

AN:

251220

AF XY:

0.00961

show subpopulations

Gnomad AFR exome

AF:

0.000986

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0569

Gnomad NFE exome

AF:

0.00769

Gnomad OTH exome

AF:

0.00929

GnomAD4 exome

AF:

0.00768

AC:

11228

AN:

1461714

Hom.:

136

Cov.:

AF XY:

0.00753

AC XY:

5479

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.000926

AC:

AN:

33480

American (AMR)

AF:

0.00172

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00457

AC:

394

AN:

86258

European-Finnish (FIN)

AF:

0.0552

AC:

2938

AN:

53246

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00661

AC:

7355

AN:

1112006

Other (OTH)

AF:

0.00631

AC:

381

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

781

1562

2344

3125

3906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

280

560

840

1120

1400

<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:

0.00799

AC:

1217

AN:

152320

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

769

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41576

American (AMR)

AF:

0.00229

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0596

AC:

633

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00681

AC:

463

AN:

68020

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00573

Hom.:

Bravo

AF:

0.00382

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00686

AC:

ExAC

AF:

0.00836

AC:

1015

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00682

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Microcytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

PhyloP100

7.3

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.5

REVEL

Benign

0.14

Sift

Benign

0.060

Sift4G

Uncertain

0.041

Polyphen

0.88

Vest4

0.51

MVP

0.67

MPC

0.30

ClinPred

0.021

GERP RS

5.3

Varity_R

0.17

gMVP

0.39

Mutation Taster

=97/3

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