chr11-8964218-G-C

Variant names:

• chr11-8964218-G-C
• rs1278142668
• NM_020644.3:c.96C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020644.3(TMEM9B):​c.96C>G​(p.Asp32Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,676 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TMEM9B NM_020644.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.552
• Publications: 0 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]

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

ACMG classification

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=0.058608353).

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.96C>G	p.Asp32Glu	missense	Exon 1 of 5	NP_065695.1	Q9NQ34-1
	TMEM9B	NM_001286094.2		c.-35C>G		5_prime_UTR	Exon 1 of 4	NP_001273023.1	Q9NQ34-2
	TMEM9B	NM_001286095.2		c.-118+672C>G		intron	N/A	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.96C>G	p.Asp32Glu	missense	Exon 1 of 5	ENSP00000433361.1	Q9NQ34-1
	TMEM9B	ENST00000309134.9	TSL:1	c.-35C>G		5_prime_UTR	Exon 1 of 4	ENSP00000311842.5	Q9NQ34-2
	TMEM9B	ENST00000931334.1		c.96C>G	p.Asp32Glu	missense	Exon 1 of 5	ENSP00000601393.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428676 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 707856

African (AFR) AF: 0.00 AC: 0 AN: 32692

American (AMR) AF: 0.00 AC: 0 AN: 39818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.00 AC: 0 AN: 37992

South Asian (SAS) AF: 0.00 AC: 0 AN: 81570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096392

Other (OTH) AF: 0.00 AC: 0 AN: 59128

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.55
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.047
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.030	B
Vest4		0.12
MutPred		0.17		Gain of ubiquitination at K35 (P = 0.078)
MVP		0.068
MPC		0.45
ClinPred		0.16	T
GERP RS		3.3
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.49
Mutation Taster		=91/9	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: rs1278142668; hg19: chr11-8985765;