Genetic Variant TMPRSS6:p.Ile421Lys (chr22-37084229-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000442782.7(TMPRSS6):c.1262T>A(p.Ile421Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I421T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 8.5e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMPRSS6
ENST00000442782.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.812

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14978859).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000442782.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TMPRSS6	NM_001374504.1	MANE Select	c.1196+66T>A	intron	N/A	NP_001361433.1
TMPRSS6	NM_001289000.2		c.1196+66T>A	intron	N/A	NP_001275929.1
TMPRSS6	NM_001289001.2		c.1196+66T>A	intron	N/A	NP_001275930.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TMPRSS6	ENST00000442782.7	TSL:1	c.1262T>A	p.Ile421Lys	missense	Exon 10 of 10	ENSP00000397691.3
TMPRSS6	ENST00000676104.1	MANE Select	c.1196+66T>A		intron	N/A	ENSP00000501573.1
TMPRSS6	ENST00000406856.7	TSL:1	c.1196+66T>A		intron	N/A	ENSP00000384964.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148186

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

8.45e-7

AC:

AN:

1183340

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

594928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27350

American (AMR)

AF:

0.0000276

AC:

AN:

36200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22722

East Asian (EAS)

AF:

0.00

AC:

AN:

33092

South Asian (SAS)

AF:

0.00

AC:

AN:

76198

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5172

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

883760

Other (OTH)

AF:

0.00

AC:

AN:

49916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

148186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72140

African (AFR)

AF:

0.00

AC:

AN:

40340

American (AMR)

AF:

0.00

AC:

AN:

14908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

4652

South Asian (SAS)

AF:

0.00

AC:

AN:

4466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67056

Other (OTH)

AF:

0.00

AC:

AN:

2072

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.21

(source)

DANN

Benign

0.48

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0075

LIST_S2

Benign

0.21

M_CAP

Benign

0.0027

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.94

PhyloP100

-0.81

PROVEAN

Benign

0.52

REVEL

Benign

0.083

Sift

Benign

0.16

Sift4G

Benign

0.23

Vest4

0.28

MutPred

0.48

Gain of solvent accessibility (P = 4e-04)

MVP

0.69

ClinPred

0.15

GERP RS

-1.9

Mutation Taster

=100/0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over