Variant 11-8948415-C-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000534025.6(TMEM9B):c.502G>A(p.Val168Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TMEM9B
ENST00000534025.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.02

Variant links:

Genes affected

TMEM9B (HGNC:1168): (TMEM9 domain family member B) Involved in positive regulation of I-kappaB kinase/NF-kappaB signaling. Predicted to be located in early endosome membrane and lysosomal membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM9B 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=0.24657878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM9B	NM_020644.3 linkuse as main transcript	c.502G>A	p.Val168Met	missense_variant	5/5	ENST00000534025.6	NP_065695.1	Q9NQ34-1Q543A1
TMEM9B	NM_001286094.2 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	4/4		NP_001273023.1	Q9NQ34-2
TMEM9B	NM_001286095.2 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	5/5		NP_001273024.1	Q9NQ34-2B7Z6P5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM9B	ENST00000534025.6 linkuse as main transcript	c.502G>A	p.Val168Met	missense_variant	5/5	1	NM_020644.3	ENSP00000433361.1	Q9NQ34-1
TMEM9B	ENST00000309134.9 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	4/4	1		ENSP00000311842.5	Q9NQ34-2
TMEM9B	ENST00000525069.5 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	5/5	2		ENSP00000431487.1	Q9NQ34-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251406

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

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 submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.502G>A (p.V168M) alteration is located in exon 5 (coding exon 5) of the TMEM9B gene. This alteration results from a G to A substitution at nucleotide position 502, causing the valine (V) at amino acid position 168 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

0.23

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

.;T;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Benign

0.0024

MetaRNN

Benign

0.25

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.0

.;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.059

T;T;T

Sift4G

Benign

0.16

T;T;T

Polyphen

0.16

.;B;.

Vest4

0.11

MutPred

0.76

.;Gain of disorder (P = 0.1102);.;

MVP

0.082

MPC

0.55

ClinPred

0.078

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.62

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