Variant chr11-8964218-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000534025.6(TMEM9B):c.96C>A(p.Asp32Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM9B
ENST00000534025.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.552

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.057489157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM9B	NM_020644.3 linkuse as main transcript	c.96C>A	p.Asp32Glu	missense_variant	1/5	ENST00000534025.6	NP_065695.1	Q9NQ34-1Q543A1
TMEM9B	NM_001286094.2 linkuse as main transcript	c.-35C>A		5_prime_UTR_variant	1/4		NP_001273023.1	Q9NQ34-2
TMEM9B	NM_001286095.2 linkuse as main transcript	c.-118+672C>A		intron_variant			NP_001273024.1	Q9NQ34-2B7Z6P5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM9B	ENST00000534025.6 linkuse as main transcript	c.96C>A	p.Asp32Glu	missense_variant	1/5	1	NM_020644.3	ENSP00000433361.1		Q9NQ34-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1428676

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707856

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

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

Sep 14, 2022

The c.96C>A (p.D32E) alteration is located in exon 1 (coding exon 1) of the TMEM9B gene. This alteration results from a C to A substitution at nucleotide position 96, causing the aspartic acid (D) at amino acid position 32 to be replaced by a glutamic acid (E). 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

0.090

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Benign

0.021

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.42

M_CAP

Benign

0.010

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

MutationTaster

Benign

1.0

D;D;D;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.50

REVEL

Benign

0.073

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.030

Vest4

0.12

MutPred

0.17

Gain of ubiquitination at K35 (P = 0.078);

MVP

0.068

MPC

0.45

ClinPred

0.15

GERP RS

3.3

Varity_R

0.12

gMVP

0.49

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