Genetic Variant TMPRSS6:p.Lys244Gln (chr22-37089684-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001374504.1(TMPRSS6):c.730A>C(p.Lys244Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K244E) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03629136).

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>C	p.Lys244Gln	missense	Exon 7 of 18	NP_001361433.1
TMPRSS6	NM_001289000.2		c.730A>C	p.Lys244Gln	missense	Exon 7 of 19	NP_001275929.1
TMPRSS6	NM_001289001.2		c.730A>C	p.Lys244Gln	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>C	p.Lys244Gln	missense	Exon 7 of 18	ENSP00000501573.1
TMPRSS6	ENST00000406856.7	TSL:1	c.730A>C	p.Lys244Gln	missense	Exon 7 of 19	ENSP00000384964.1
TMPRSS6	ENST00000346753.9	TSL:1	c.730A>C	p.Lys244Gln	missense	Exon 7 of 18	ENSP00000334962.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1459316

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725720

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

85814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111006

Other (OTH)

AF:

0.00

AC:

AN:

60274

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

39624

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.011

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.062

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.16

M_CAP

Benign

0.017

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.76

PhyloP100

-1.7

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.33

REVEL

Benign

0.020

Sift

Benign

0.23

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.085

MutPred

0.28

Gain of sheet (P = 0.0221)

MVP

0.34

MPC

0.17

ClinPred

0.26

GERP RS

-9.2

Varity_R

0.049

gMVP

0.43

Mutation Taster

=98/2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over