chr11-8948448-C-T

Variant names:

• chr11-8948448-C-T
• rs770760054
• NM_020644.3:c.469G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020644.3(TMEM9B):​c.469G>A​(p.Asp157Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TMEM9B NM_020644.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13548839).

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.469G>A	p.Asp157Asn	missense	Exon 5 of 5	NP_065695.1	Q9NQ34-1
	TMEM9B	NM_001286094.2		c.247G>A	p.Asp83Asn	missense	Exon 4 of 4	NP_001273023.1	Q9NQ34-2
	TMEM9B	NM_001286095.2		c.247G>A	p.Asp83Asn	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.469G>A	p.Asp157Asn	missense	Exon 5 of 5	ENSP00000433361.1	Q9NQ34-1
	TMEM9B	ENST00000309134.9	TSL:1	c.247G>A	p.Asp83Asn	missense	Exon 4 of 4	ENSP00000311842.5	Q9NQ34-2
	TMEM9B	ENST00000931334.1		c.460G>A	p.Asp154Asn	missense	Exon 5 of 5	ENSP00000601393.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251136 AF XY: 0.0000295

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461674 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727138

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111898

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N
PhyloP100		5.4
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.077
Sift	Benign	0.43	T
Sift4G	Benign	0.81	T
Polyphen		0.056	B
Vest4		0.10
MutPred		0.34		Gain of MoRF binding (P = 0.0467)
MVP		0.082
MPC		0.51
ClinPred		0.10	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.085
gMVP		0.53
Mutation Taster		=69/31	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: rs770760054; hg19: chr11-8969995; COSMIC: COSV58427115; COSMIC: COSV58427115;