11-8948415-C-G

Variant names:

• chr11-8948415-C-G
• rs764636398
• NM_020644.3:c.502G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020644.3(TMEM9B):​c.502G>C​(p.Val168Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V168M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM9B NM_020644.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM9B	NM_020644.3	MANE Select	c.502G>C	p.Val168Leu	missense	Exon 5 of 5	NP_065695.1	Q9NQ34-1
	TMEM9B	NM_001286094.2		c.280G>C	p.Val94Leu	missense	Exon 4 of 4	NP_001273023.1	Q9NQ34-2
	TMEM9B	NM_001286095.2		c.280G>C	p.Val94Leu	missense	Exon 5 of 5	NP_001273024.1	Q9NQ34-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM9B	ENST00000534025.6	TSL:1 MANE Select	c.502G>C	p.Val168Leu	missense	Exon 5 of 5	ENSP00000433361.1	Q9NQ34-1
	TMEM9B	ENST00000309134.9	TSL:1	c.280G>C	p.Val94Leu	missense	Exon 4 of 4	ENSP00000311842.5	Q9NQ34-2
	TMEM9B	ENST00000931334.1		c.493G>C	p.Val165Leu	missense	Exon 5 of 5	ENSP00000601393.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0064	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.042	D
Polyphen		0.062	B
Vest4		0.43
MutPred		0.78		Loss of catalytic residue at V168 (P = 0.0626)
MVP		0.20
MPC		0.71
ClinPred		0.88	D
GERP RS		6.1
Varity_R		0.34
gMVP		0.58
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs764636398; hg19: chr11-8969962;