22-37066133-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001374504.1(TMPRSS6):​c.2356G>A​(p.Val786Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0101 in 1,613,366 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0083 ( 4 hom., cov: 33)
Exomes 𝑓: 0.010 ( 96 hom. )

Consequence

TMPRSS6
NM_001374504.1 missense

Scores

1
7
10

Clinical Significance

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

Conservation

PhyloP100: 6.05
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.017411858).
BP6
Variant 22-37066133-C-T is Benign according to our data. Variant chr22-37066133-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr22-37066133-C-T is described in Lovd as [Likely_benign]. Variant chr22-37066133-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00829 (1262/152222) while in subpopulation NFE AF= 0.01 (680/67978). AF 95% confidence interval is 0.00938. There are 4 homozygotes in gnomad4. There are 627 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMPRSS6NM_001374504.1 linkc.2356G>A p.Val786Ile missense_variant Exon 18 of 18 ENST00000676104.1 NP_001361433.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMPRSS6ENST00000676104.1 linkc.2356G>A p.Val786Ile missense_variant Exon 18 of 18 NM_001374504.1 ENSP00000501573.1 Q8IU80-1

Frequencies

GnomAD3 genomes
AF:
0.00830
AC:
1263
AN:
152104
Hom.:
4
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00773
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00170
Gnomad ASJ
AF:
0.00519
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0200
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0100
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.00805
AC:
2008
AN:
249464
Hom.:
16
AF XY:
0.00799
AC XY:
1081
AN XY:
135254
show subpopulations
Gnomad AFR exome
AF:
0.00833
Gnomad AMR exome
AF:
0.00122
Gnomad ASJ exome
AF:
0.00518
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.0177
Gnomad NFE exome
AF:
0.0120
Gnomad OTH exome
AF:
0.00801
GnomAD4 exome
AF:
0.0103
AC:
15005
AN:
1461144
Hom.:
96
Cov.:
32
AF XY:
0.00982
AC XY:
7138
AN XY:
726864
show subpopulations
Gnomad4 AFR exome
AF:
0.00747
Gnomad4 AMR exome
AF:
0.00150
Gnomad4 ASJ exome
AF:
0.00589
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000255
Gnomad4 FIN exome
AF:
0.0166
Gnomad4 NFE exome
AF:
0.0118
Gnomad4 OTH exome
AF:
0.00758
GnomAD4 genome
AF:
0.00829
AC:
1262
AN:
152222
Hom.:
4
Cov.:
33
AF XY:
0.00842
AC XY:
627
AN XY:
74444
show subpopulations
Gnomad4 AFR
AF:
0.00768
Gnomad4 AMR
AF:
0.00170
Gnomad4 ASJ
AF:
0.00519
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0200
Gnomad4 NFE
AF:
0.0100
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00898
Hom.:
11
Bravo
AF:
0.00758
TwinsUK
AF:
0.00998
AC:
37
ALSPAC
AF:
0.0112
AC:
43
ESP6500AA
AF:
0.00931
AC:
41
ESP6500EA
AF:
0.00954
AC:
82
ExAC
AF:
0.00850
AC:
1032
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00829
EpiControl
AF:
0.00990

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:3
May 22, 2019
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Jan 13, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 10, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS1, BS2 -

Aug 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TMPRSS6: BS1, BS2 -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Microcytic anemia Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T;.;.;.
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.78
T;D;T;.
MetaRNN
Benign
0.017
T;T;T;T
MetaSVM
Uncertain
0.58
D
MutationAssessor
Benign
1.2
L;.;.;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-0.64
N;N;N;N
REVEL
Uncertain
0.62
Sift
Benign
0.050
D;D;D;D
Sift4G
Benign
0.11
T;T;T;T
Polyphen
1.0
D;D;.;D
Vest4
0.29
MVP
0.95
MPC
0.60
ClinPred
0.013
T
GERP RS
4.5
Varity_R
0.13
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs139105452; hg19: chr22-37462173; COSMIC: COSV100696245; COSMIC: COSV100696245; API