13-99559463-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004800.3(TM9SF2):​c.1853C>T​(p.Thr618Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

TM9SF2
NM_004800.3 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68
Variant links:
Genes affected
TM9SF2 (HGNC:11865): (transmembrane 9 superfamily member 2) This gene encodes a member of the transmembrane 9 superfamily. The encoded 76 kDa protein localizes to early endosomes in human cells. The encoded protein possesses a conserved and highly hydrophobic C-terminal domain which contains nine transmembrane domains. The protein may play a role in small molecule transport or act as an ion channel. A pseudogene associated with this gene is located on the X chromosome. [provided by RefSeq, Oct 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3816059).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TM9SF2NM_004800.3 linkuse as main transcriptc.1853C>T p.Thr618Met missense_variant 16/17 ENST00000376387.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TM9SF2ENST00000376387.5 linkuse as main transcriptc.1853C>T p.Thr618Met missense_variant 16/171 NM_004800.3 P1
TM9SF2ENST00000642475.1 linkuse as main transcriptc.1853C>T p.Thr618Met missense_variant 18/19 P1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152136
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000162
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251326
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135840
show subpopulations
Gnomad AFR exome
AF:
0.000123
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:
0.000114
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000170
AC:
248
AN:
1461692
Hom.:
0
Cov.:
30
AF XY:
0.000169
AC XY:
123
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000216
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152136
Hom.:
0
Cov.:
32
AF XY:
0.0000807
AC XY:
6
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000965
Hom.:
0
Bravo
AF:
0.000106
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 23, 2023The c.1853C>T (p.T618M) alteration is located in exon 16 (coding exon 16) of the TM9SF2 gene. This alteration results from a C to T substitution at nucleotide position 1853, causing the threonine (T) at amino acid position 618 to be replaced by a methionine (M). 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
0.11
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.31
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.25
T;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Benign
0.65
D
LIST_S2
Uncertain
0.89
.;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.38
T;T
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Pathogenic
3.6
H;H
MutationTaster
Benign
0.90
D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.4
.;N
REVEL
Benign
0.24
Sift
Uncertain
0.0040
.;D
Sift4G
Uncertain
0.013
.;D
Polyphen
0.98
D;D
Vest4
0.42
MVP
0.37
MPC
0.94
ClinPred
0.58
D
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.24
gMVP
0.59

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.

Other links and lift over

dbSNP: rs760637508; hg19: chr13-100211717; COSMIC: COSV64506727; API