Genetic Variant NM_020644.3:c.96C>A (chr11-8964218-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_020644.3(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. 15/21 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
NM_020644.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.552

Publications

0 publications found

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:

TMEM9B-AS1 (HGNC:19230): (TMEM9B antisense RNA 1)

TMEM9B-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020644.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM9B	NM_020644.3	MANE Select	c.96C>A	p.Asp32Glu	missense	Exon 1 of 5	NP_065695.1	Q9NQ34-1
TMEM9B	NM_001286094.2		c.-35C>A		5_prime_UTR	Exon 1 of 4	NP_001273023.1	Q9NQ34-2
TMEM9B	NM_001286095.2		c.-118+672C>A		intron	N/A	NP_001273024.1	Q9NQ34-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM9B	ENST00000534025.6	TSL:1 MANE Select	c.96C>A	p.Asp32Glu	missense	Exon 1 of 5	ENSP00000433361.1	Q9NQ34-1
TMEM9B	ENST00000309134.9	TSL:1	c.-35C>A		5_prime_UTR	Exon 1 of 4	ENSP00000311842.5	Q9NQ34-2
TMEM9B	ENST00000931334.1		c.96C>A	p.Asp32Glu	missense	Exon 1 of 5	ENSP00000601393.1

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

African (AFR)

AF:

0.00

AC:

AN:

32692

American (AMR)

AF:

0.00

AC:

AN:

39818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25476

East Asian (EAS)

AF:

0.00

AC:

AN:

37992

South Asian (SAS)

AF:

0.00

AC:

AN:

81570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1096392

Other (OTH)

AF:

0.00

AC:

AN:

59128

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

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

PhyloP100

0.55

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

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.12

gMVP

0.49

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over