dbSNP rs115310908: TMPRSS6:p.Arg702Leu (chr22-37069081-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001374504.1(TMPRSS6):c.2105G>T(p.Arg702Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,543,202 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0042 ( 5 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 5 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.667

Publications

1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009433091).

BP6

Variant 22-37069081-C-A is Benign according to our data. Variant chr22-37069081-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 341580.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00418 (637/152372) while in subpopulation AFR AF = 0.0149 (618/41582). AF 95% confidence interval is 0.0139. There are 5 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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.2105G>T	p.Arg702Leu	missense	Exon 16 of 18	NP_001361433.1	Q8IU80-1
TMPRSS6	NM_001289000.2		c.2105G>T	p.Arg702Leu	missense	Exon 16 of 19	NP_001275929.1	Q8IU80-5
TMPRSS6	NM_001289001.2		c.2105G>T	p.Arg702Leu	missense	Exon 16 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.2105G>T	p.Arg702Leu	missense	Exon 16 of 18	ENSP00000501573.1	Q8IU80-1
TMPRSS6	ENST00000406856.7	TSL:1	c.2105G>T	p.Arg702Leu	missense	Exon 16 of 19	ENSP00000384964.1	Q8IU80-5
TMPRSS6	ENST00000346753.9	TSL:1	c.2105G>T	p.Arg702Leu	missense	Exon 16 of 18	ENSP00000334962.6	Q8IU80-1

Frequencies

GnomAD3 genomes

AF:

0.00418

AC:

637

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00101

AC:

143

AN:

141312

AF XY:

0.000714

show subpopulations

Gnomad AFR exome

AF:

0.0174

Gnomad AMR exome

AF:

0.000431

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.000714

GnomAD4 exome

AF:

0.000436

AC:

606

AN:

1390830

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

248

AN XY:

686868

show subpopulations

African (AFR)

AF:

0.0167

AC:

529

AN:

31708

American (AMR)

AF:

0.000463

AC:

AN:

36678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.00

AC:

AN:

35954

South Asian (SAS)

AF:

0.0000754

AC:

AN:

79614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4774

European-Non Finnish (NFE)

AF:

0.00000647

AC:

AN:

1081414

Other (OTH)

AF:

0.000811

AC:

AN:

57952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00418

AC:

637

AN:

152372

Hom.:

Cov.:

AF XY:

0.00396

AC XY:

295

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0149

AC:

618

AN:

41582

American (AMR)

AF:

0.000653

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00422

Hom.:

Bravo

AF:

0.00436

ESP6500AA

AF:

0.0126

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.000797

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Microcytic anemia (1)

TMPRSS6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

Eigen

Benign

-0.084

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0094

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.1

PhyloP100

0.67

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.44

Sift

Uncertain

0.027

Sift4G

Benign

0.082

Polyphen

0.82

Vest4

0.48

MVP

0.91

MPC

0.39

ClinPred

0.030

GERP RS

3.6

Varity_R

0.38

gMVP

0.65

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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