Variant chr22-37066211-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001374504.1(TMPRSS6):c.2278A>C(p.Lys760Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15693104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS6	NM_001374504.1 linkuse as main transcript	c.2278A>C	p.Lys760Gln	missense_variant	18/18	ENST00000676104.1	NP_001361433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS6	ENST00000676104.1 linkuse as main transcript	c.2278A>C	p.Lys760Gln	missense_variant	18/18		NM_001374504.1	ENSP00000501573	P1	Q8IU80-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000811

AC:

AN:

246614

Hom.:

AF XY:

0.00000746

AC XY:

AN XY:

134106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460400

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726454

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2023

The c.2305A>C (p.K769Q) alteration is located in exon 18 (coding exon 18) of the TMPRSS6 gene. This alteration results from a A to C substitution at nucleotide position 2305, causing the lysine (K) at amino acid position 769 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.71

T;T;T;.

M_CAP

Benign

0.067

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-0.38

N;.;.;.

MutationTaster

Benign

0.96

N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.34

N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.55

T;T;T;T

Sift4G

Benign

0.65

T;T;T;T

Polyphen

0.0080

B;B;.;B

Vest4

0.092

MutPred

0.61

Loss of methylation at K769 (P = 0.0033);.;.;.;

MVP

0.76

MPC

0.20

ClinPred

0.19

GERP RS

4.5

Varity_R

0.15

gMVP

0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over