12-3281306-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006675.5(TSPAN9):​c.541G>A​(p.Ala181Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,550,776 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

TSPAN9
NM_006675.5 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0950
Variant links:
Genes affected
TSPAN9 (HGNC:21640): (tetraspanin 9) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. Alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Nov 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.022229433).
BP6
Variant 12-3281306-G-A is Benign according to our data. Variant chr12-3281306-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3183856.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSPAN9NM_006675.5 linkc.541G>A p.Ala181Thr missense_variant 7/9 ENST00000011898.10 NP_006666.1 O75954

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSPAN9ENST00000011898.10 linkc.541G>A p.Ala181Thr missense_variant 7/91 NM_006675.5 ENSP00000011898.5 O75954

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152226
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
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
GnomAD3 exomes
AF:
0.0000708
AC:
11
AN:
155418
Hom.:
0
AF XY:
0.0000610
AC XY:
5
AN XY:
81924
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000975
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000172
AC:
24
AN:
1398550
Hom.:
0
Cov.:
32
AF XY:
0.0000159
AC XY:
11
AN XY:
689768
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000420
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000556
Gnomad4 OTH exome
AF:
0.0000517
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152226
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000385
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000143
AC:
1

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 11, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
5.1
DANN
Benign
0.97
DEOGEN2
Benign
0.068
T;T;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.045
N
LIST_S2
Benign
0.83
T;.;T;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.022
T;T;T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
0.32
N;N;.;.
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.30
N;N;.;N
REVEL
Benign
0.084
Sift
Benign
0.83
T;T;.;T
Sift4G
Benign
0.63
T;T;.;T
Polyphen
0.0020
B;B;.;.
Vest4
0.072
MutPred
0.42
Gain of catalytic residue at A181 (P = 0.0011);Gain of catalytic residue at A181 (P = 0.0011);.;Gain of catalytic residue at A181 (P = 0.0011);
MVP
0.12
MPC
0.50
ClinPred
0.015
T
GERP RS
-3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.020
gMVP
0.69

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: rs747741255; hg19: chr12-3390472; API